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Signal integration by jnk and p38 mapk pathways in cancer development

Signal integration by JNK and p38 MAPK pathways in cancer developmentErwin F. Wagner and Ángel R. Nebreda Abstract Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) family members function in a cell context-specific and cell type-specific manner to integrate signals that affect proliferation, differentiation, survival and migration. Consistent with the importance of these events in tumorigenesis, JNK and p38 MAPK signalling is associated with cancers in humans and mice. Studies in mouse models have been essential to better understand how these MAPKs control cancer development, and these models are expected to provide new strategies for the design of improved therapeutic approaches. In this Review we highlight the recent progress made in defining the functions of the JNK and p38 MAPK pathways in different cancers.
Mitogen-activated protein kinases (MAPKs) are signalling therapeutic applications. This Review aims to describe components that are important in converting extracel- the progress made in determining the role of JNK and lular stimuli into a wide range of cel ular responses. The p38 MAPK signalling in cancers, drawing together and MAPKs are activated by mitogens insights from mouse models and human cancer, and also and were found to be upregulated in human tumours; attempts to answer some of the open questions remaining this finding has led to the development of inhibitors in the field of MAPK signalling.
of this pathway for cancer therapeutics1. Two other major MAPK pathways, the Jun N-terminal kinase (JNK) Signalling by MAPKs
and p38 MAPK pathways, which are also called stress- MAPKs are evolutionarily conserved enzymes, the activated protein kinase pathways, are also often deregu- activation of which requires dual phosphorylation on lated in cancers. JNKs and p38 MAPKs are activated by the Thr-X-Tyr motif that is catalysed by MAP2K kinases environmental and genotoxic stresses and have key roles (FIG. 1). After activation, MAPKs phosphorylate specific in inflammation, as well as in tissue homeostasis, as they serine and threonine residues of target substrates, which control cell proliferation, differentiation, survival and include other protein kinases and many transcription the migration of specific cell types2–6. The functions of factors. MAPKs are switched off by both generic phos- JNKs and p38 MAPKs in cancer development are com- phatases and dual-specificity phosphatases and are fur- plex, which is consistent with the wide range of cel ular ther regulated by scaffold proteins, which are usual y responses that they modulate. Certain cel s use these specific for each of the three major mammalian MAPK signalling pathways to antagonize cell proliferation and pathways7–9.
morphological transformation, whereas cancer cel s can subvert these pathways to facilitate proliferation, sur- JNK signal ing. The JNK proteins are encoded by three
vival and invasion. A molecular understanding of how gen (which enco(which JNK and p38 MAPK family members and their isoforms encodes and (which encodes ), Centro Nacional de Investigaciones Oncológicas, function either as tumour suppressors or oncoproteins in which are alternatively spliced giving rise to at least ten C/Melchor Fernández specific cell types is largely missing. Moreover, the extent isoforms10. JNK1 and JNK2 are expressed in almost every Almagro 3, 28029 Madrid, of redundancy and crosstalk between these signalling cel , whereas JNK3 is mainly found in the brain11,12. JNKs pathways and the consequent physiological implications can be activated by the upstream and are poorly understood. One major challenge will be to kinases (FIG. 1). Although there are many JNK substrates, determine how, when and where specific targeting of the it is still a challenge to identify the molecular networks JNK and p38 MAPK pathways should be considered for regulated by the individual JNK family members4–6. NATuRE REviEws CanCer
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2009 Macmillan Publishers Limited. All rights reserved (), MAP kinase-interacting serine/threonine At a glance
kinase 1 () an(REFs 17,18) (FIG. 1). There • Jun N-terminal kinases (JNKs) and p38 mitogen-activated protein kinases (MAPKs) is much evidence to support a role for p38α as a tumour have important roles in the signalling mechanisms that orchestrate cellular responses suppressor, and this function of p38α is mostly mediated to many types of stresses, but also control the proliferation, differentiation, survival by both negative regulation of cell cycle progression and and migration of specific cell types.
the induction of apoptosis, although the induction of • JNKs and p38 MAPKs can exert antagonistic effects on cell proliferation and survival, terminal differentiation also contributes to its tumour- which depend on cell type-specific differences, as well as on the intensity and suppressive function20–22. However, p38α may also have duration of the signal and the crosstalk between other signalling pathways.
oncogenic functions that are mediated by its involvement • Crosstalk between the JNK and p38 MAPK pathways is emerging as an important in key processes of cancer progression, such as invasion, regulatory mechanism in many cellular responses.
inflammation and angiogenesis.
• The JNK and p38 MAPK pathways regulate the activity and expression of key inflammatory mediators, including cytokines and proteases, which may function as Proliferation, survival and differentiation
potent cancer promoters.
unscheduled proliferation is a hallmark of cancer, and the • The specific role of individual JNK and p38 MAPK family members in particular JNK and p38 MAPK pathways regulate cell cycle progres- cellular processes in vivo has been addressed by gene-targeting experiments in mice. sion at different transition points by both transcription- Genetically engineered mouse models have confirmed the importance of these dependent and transcription-independent mechanisms. pathways for tumorigenesis in various organs.
in addition, both pathways modulate the cel ular pro- • The expression or activity of JNK and p38 MAPK pathway components is often altered grammes for cell survival and differentiation, with in human tumours and cancer cell lines. Given the many tumorigenesis-related profound effects on the development of various cancers.
functions that these kinases can control, both in the cancer cell and in the tumour microenvironment, it is important to carefully consider the type of tumour before attempting to modulate these pathways for cancer therapy.
Role of JNKs. Depending on the stimuli and the strength
and duration of JNK activation, the cel ular response has diverse outcomes, which range from the induction of A major JNK target is the transcription factor AP1, which apoptosis to increased survival and altered proliferation. is composed of Fos and Jun family members13. The onco- As studies on JNK activation use a wide range of experi- genic functions of JNKs are mostly based on their ability mental settings and genetical y altered cel s, the mes- to phosphorylate JuN and to activate AP1, whereas their sages emerging from these studies and the consequent tumour-suppressive functions are probably related to their implications for cancer development are complex4,5,12,22.
pro-apoptotic activity. The JNK/JuN pathway regulates a Because different JNKs differ substantial y in their plethora of target genes that contain AP1-binding sites, ability to interact with JuN, a well-established regulator including genes that control the cell cycle, as well as sur- of cell cycle progression13, these kinases have profound vival and apoptosis, metalloproteinases and nuclear hor- effects on cell proliferation5,23,24. in non-stimulated cel s, mone receptors, such as retinoid receptors14. in addition, JNK2 seems to mainly target JuN for degradation, factors such as the signal intensity and crosstalk between whereas following stimulation, JNK1 phosphorylates different JNK isoforms are important for the overall effect and stabilizes JuN leading to transcriptional activation25. of JNK activation on tumour development4,5,12.
Consequently, compared with wild-type fibroblasts, JNK2-knockout fibroblasts grow slightly faster, whereas p38 MAPK signal ing. There are four genes that encode JNK1-knockout cel s grow slower, a phenotype that is
p38 MAP (which encocorrelated with reduced AP1 activity and decreased JuN (which enco (which enco) phosphorylation23. The opposing roles of JNK1 and JNK2 and (which encodes two alternatively in proliferation have also been observed in erythrocytes spliced isoforms of MAPK14 have also been reported15,16. and keratinocytes23. interestingly, it has also been pro- p38α and p38β are closely related proteins that could have posed that increased expression of JuN and the increased overlapping functions. whereas p38α is highly abundant proliferation of JNK2-knockout fibroblasts are prima- in most cell types, p38β seems to be expressed at very rily due to compensatory increases in JNK1 function26. low levels, and its contribution to p38 MAPK signalling Conditional genetic experiments in different tissues and is not clear. p38γ and p38δ have more restricted expres- cel s are necessary to better define the molecular mecha- sion patterns and are likely to have specialized functions. nism of JNK functions. Recently, the JNK pathway was Most of the published literature on p38 MAPKs refers linked to p53-dependent senescence using a conditional A dimeric transcription factor to p38α17,18.
JNK1 allele27. The role of the JNK/JuN pathway as a nega- complex that contains p38 MAPKs are activated by the upstream tive regulator of the p53 tumour suppressor also supports members of the Jun, Fos, Atf and kinases, and sometimes by MKK4 (FIG. 1); the oncogenic role of activated JNK in tumour models.
and Maf protein families. autophosphorylation may also contribute to p38 MAPK A role for JNKs in cell survival is well established, Expression of these ‘immediate early genes' is activation18,19. The two major groups of proteins that are although the proposed underlying mechanisms are con- often low or undetectable in regulated by p38 MAPK-mediated phosphorylation troversial5. As cytoplasmic injection of cytochrome c quiescent cells, but activated are transcription factors, such aactivating transcrip- rescued the apoptotic defects of JNK-deficient fibro- in minutes following tion factor 2 (yocyte-specific enhancer blasts, JNK pro-apoptotic functions were proposed to extracellular stimulation, such factor 2 (MEF2) and ; and protein kinases, be mediated by the mitochondrial pathway28. JNKs can as the addition of a growth factor or ultraviolet including MAPK-activated kinase 2 also known as both phosphorylate and regulate the expression of sev- irrradiation and other stresses.
MAPK2), mitogen- and stress-activated protein kinase 1 eral members of the Bcl-2 protein family, such as 538 AugusT 2009 vOluME 9
2009 Macmillan Publishers Limited. All rights reserved and Bcl2 antagonist of cell death ), as well as 14-3-3 proteins (FIG. 1). Phosphorylation of 14-3-3 proteins by JNKs releases pro-apoptotic proteins, such as BAX and FOXO transcription factors, from inactive complexes, thereby facilitating JNK-mediated apoptosis5.
The pro- or anti-apoptotic effects of JNKs, which have mostly been determined using studies in fibroblasts, seem to be dependent not only on the stimuli (for example, LZK, MEKK1, MEKK2, MEKK4, TAO1, TAO2, MLK1, MLK2 and MLK4 growth factor stimulation and ultraviolet (uv) irradia- ZAK, TAK1 and MEKK3 tion29) and tissue specificity, but also on the strength of the signal. whereas transient JNK activation was shown to promote cell survival, prolonged JNK activation mediates tumour necrosis factor-α (-dependent apoptosis, often through distincactivation pathways30. One pathway that has been suggested involves the E3 JNK1 and JNK2 JNK3 ubiquitin ligase which degrades the caspase 8 inhibitor CAsP8 and FADD-like apoptosis regulator ; also known as FliP) through JNK1 phos- phorylation of iTCH31. Another mechanism for JNK- mediated apoptosis following TNFα signalling involves caspase 8-independent cleavage of BH3-interacting domain death agonist (BiD), which relieves inhibition of caspase 8 activation by TNF receptor-associated factor 2 (TRAF2)– iAP1 (also known as BiRC2)32. However, caspase 8 can also be activated through sMAC (also Nucleus known as DiABlO), which auto-degrades iAP1 and iAP2 independently of CFlAR33.
Biological responses Compared with the well-defined molecular functions of p38 MAPKs, little is known about how JNKs control Figure 1 activation of mitogen-activated protein
kinase signalling pathways.
Mitogen-activated cell differentiation. in development, JNK1 and JNK2 control the migration of epithelial cel s during eyelid kinase (MAPK) pathways are activated by environmental closure, a process that does not require cell proliferation stresses, such as ultraviolet irradiation, heat and osmotic and is probably mediated by phosphorylation of paxil- shock, genotoxic agents, anisomycin and toxins, but are lin and F-actin polymerization4,34. in adult mice, JNK1, also activated following growth factor and inflammatory but not JNK2, was shown to modulate osteoclast forma- cytokine stimulation. The different upstream activators of Jun N-terminal kinases (JNKs) and p38 MAPKs, such as tion in vitro in JuN-dependent and JuN-independent MAP2K and MAP3K family members, are depicted. In ways35. JNKs have also been assigned functions in the addition, downstream targets, including transcription regulation of T lymphocyte differentiation using knock- factors and other effectors, which determine a range of out and dominant negative JNK transgenic mice6,36, as biological responses from cell proliferation, survival, well as in the nervous system4,5. The relevance of the differentiation and migration to inflammation and cancer, JNK pathway in other tissues of adult mice and in are shown. Many genes are directly regulated by these the context of tumour formation has yet to be investigated transcription factors, including genes that encode p21, (discussed below).
14-3-3, protein phosphatase 1D (PPM1D), GADD45α and some Bcl-2 family members by p53, immediate early gene Role of p38 MAPKs. p38α can negatively regulate cell cycle products such as FOS by ELK1, GADD45α, dual-specificity
phosphatases (DUSPs), cyclin D and JUN by activating progression both at the g1/s and the g2/M transitions transcription factor 2 (ATF2), interleukin-6 (IL-6) and by several mechanisms, including the downregulation of cyclooxygenase 2 (COX-2) by C/EBPβ, and DUSP1 and cyclins, upregulation of cyclin-dependent kinase (CDK) IL-10 by cAMP-responsive element binding protein (CREB). inhibitors and modulation of the tumour suppressor p53 ASK1, apoptosis signal-regulating kinase 1; DLK, dual (REFs 37,38) (FIG. 1). Moreover, p38γ has been reported leucine zipper-bearing kinase; LZK, leucine-zipper to regulate the g2 arrest induced by γ-radiation39. p38 kinase; MEF2, myocyte-specific enhancer factor 2; MAPKs can also trigger premature senescence in pri- MLK, mixed-lineage kinase; MNK1, MAP kinase-interacting mary cel s — a permanent proliferative arrest induced by serine/threonine kinase 1; TAK1, transforming growth oncogenes, such as — which has been proposed factor β-activated kinase 1; TAO, thousand-and-one amino to function as an anti-tumorigenic defence mechanism acid kinase; ZAK, leucine-zipper and sterile-α motif kinase.
by inducing p53 phosphorylation and the upregula- tion of p16 (REF. 40). interestingly, negative regulation may be mediated by negative regulation of the JNK/JuN of proliferation is emerging as a highly conserved and pathway42 or by downregulation of epidermal growth fac- important function of p38α in various types of primary tor receptor (43, depending on the cell type (FIG. 2). cel s, including cardiomyocytes, hepatocytes, fibroblasts, in contrast to p38α, p38δ has been reported to mediate haematopoietic cel s and lung cel s41–43. This effect of p38α TPA-induced epidermal cell proliferation in mice44.
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2009 Macmillan Publishers Limited. All rights reserved Although p38α activation is normal y associated with been characterized57, or by direct phosphorylation and anti-proliferative functions, there are reports — which inactivation of glycogen synthase kinase 3β (gsK3β), have mainly used chemical inhibitors — indicating that which results in the accumulation of the transcription p38α can sometimes positively regulate proliferation, for factor β-catenin58. Final y, p38α has been implicated in example in haematopoietic cel s45 and several cancer cel the g2/M checkpoint, which induces cell cycle arrest lines46–51. On a molecular level, the antagonistic effects and facilitates DNA repair. This function of p38α may of p38α on cell proliferation are probably attributable antagonize chemotherapy-induced DNA damage, which to different levels of kinase activity, together with the could also lead to apoptosis resistance in cancer cel s38. interplay between different signalling pathways2.
p38α is emerging as an important regulator of dif- The induction of apoptosis by many types of cel- ferentiation programmes in many cell types, including lular stresses also involves p38α. These effects can be embryonic stem cel s18,43,59,60. it can directly phospho- mediated by transcriptional and post-transcriptional rylate and modulate the activity of several transcrip- mechanisms, which affect either death receptors, sur- tion factors involved in tissue-specific differentiation; vival pathways or pro- and anti-apoptotic Bcl-2 pro- for example, MEF2 and (also known as TFE2α) teins. The contribution of these different mechanisms in skeletal muscle or C/EBPβ in adipocytes (FIG. 1). in to p38α-induced apoptosis is probably regulated in a addition, p38α regulates the targeting of the swi–sNF stimulus- and context-dependent manner21. Apoptotic chromatin-remodelling complex to muscle promoters, stimuli sometimes trigger p38α activation by secondary which contributes to the induction of muscle-specific routes, such as the production of reactive oxygen species gene transcription61,62. There is evidence indicating that (ROs). This mechanism is likely to be important for the p38α also has a key role in the proliferation arrest suppression of tumour initiation by p38α, which triggers that occurs at the onset of differentiation, but that it apoptosis in response to the expression of ROs-inducing is regulated by independent mechanisms41,43,63,64. p38α oncogenes in immortalized cel s52. Notably, p38β has downregulation in mice has a dramatic effect on lung been proposed to have anti-apoptotic effects in various homeostasis, probably reflecting the crucial function of cell lines and might counteract the pro-apoptotic effect p38α in the coordination of proliferation arrest with the of p38α activation53–55.
induction and maintenance of the differentiation state several studies have also described pro-survival in lung epithelial cel s42,43. The differentiation-inducing roles for p38α, which can be mediated by the induc- activity of p38α may be relevant for tumour suppres- tion of cell differentiation or by anti-apoptotic inflam- sion, as p38α activation triggers a more differentiated matory signals, such as the cytokine interleukin-6 and less transformed phenotype in rhabdomyosarcoma, (il-6), as well as by a quiescent state known as cancer renal carcinoma and colon cancer cell lines compared dormancy that may be important for cancer cells to with the same cancer cell lines in which p38α has not acquire drug resistance21,56. in addition, p38α can also been activated65–67. importantly, the immature and mediate cell survival either by regulating autophagy pro- poorly differentiated lung epithelium of p38α-deficient grammes, through downstream targets that have not yet mice highly sensitizes them to KRAs-induced lung in summary, the above information il ustrates how the tumour suppressive mechanisms of normal cel s can sometimes be switched to promote survival in cancer cel s. why p38α or JNK pathway activation induces apop- tosis in some cases, but can lead to increased survival in others, is likely to depend on cell type-specific differences, together with the intensity and duration of the signal and its crosstalk with other signalling pathways.
Fetal hematopoietic cells Crosstalk between JNK and p38 MAPK pathways
Crosstalk between different signalling pathways is a common theme in cell regulation, which is usual y highly dependent on cell context. The JNK and p38 MAPK path- ways share several upstream regulators, and accordingly Proliferation and tumorigenesis there are multiple stimuli that simultaneously activate Figure 2 Signal integration between Jun n-terminal kinases (JnKs) and p38
both pathways11 (FIG. 1). indeed, JNKs and p38 MAPKs Nature Reviews Cancer
mitogen-activated protein kinases (MaPKs). The figure depicts the crosstalk
can potential y synergize to induce AP1 transcriptional between JNK, p38α and nuclear factor kappa-B (NF-κB) signalling in different cellular activity, as p38α sometimes mediates the expression of systems from fetal hematopoietic cells to fibroblasts, hepatocytes, myoblasts and lung both JuN and its partner FOs68. Nevertheless, the two cells. In each of these cellular systems different connections are established, which stress-activated signalling pathways often have opposite determine the biological response. The figure illustrates how these networks may effects; for example, in the regulation of cardiomyo- function in a cell context- and stimulus-dependent way. Dotted lines indicate that the molecular mechanisms are not established. CFLAR, CASP8 and FADD-like apoptosis cyte hypertrophy69, in CD95-induced Jurkat cell apop- regulator; DUSP1, dual specificity protein phosphatase 1; EGFR, epidermal growth factor tosis70 and in mouse models of liver cancer42 (FIG. 2). receptor; GRAP2, GRB2-related adaptor protein 2; IKKβ, inhibitor of nuclear factor κB Further evidence for the antagonism between JNK kinase subunit-β; PPase; protein phosphatase.
and p38 MAPKs has recently been reported in mouse 540 AugusT 2009 vOluME 9
2009 Macmillan Publishers Limited. All rights reserved embryonic fibroblasts (MEFs) deficient in the JNK but correlates with increased phosphorylation of MKK3, activator MKK7 (REF. 71). The impaired activation of MKK4 and MKK6 (REF. 75). This suggests that a nega- JNKs in MKK7–/– MEFs correlates with reduced cell pro- tive feedback loop is involved at the level of an upstream liferation, augmented premature senescence and resist- MAP3K, as proposed for TAK1 and MlK3 (REFs 72,73). ance to oncogenic transformation. interestingly, all of Therefore, p38α can antagonize JNK signalling by differ- these phenotypes were reverted by treating the MEFs ent mechanisms depending on the cell type and stimulus with inhibitors of p38α and p38β71. similar results were (FIG. 2).
obtained in the context of embryonic hepatoblast pro- Mouse models of cancer have also provided evidence liferation in vitro, as well as liver regeneration after par- for the interaction of both JNK and p38 MAPKs with tial hepatectomy in vivo. The authors proposed that one the NF-κB pathway, a key regulator of cell survival and of the mechanisms underlying this crosstalk might be inflammatory processes. Hepatocytes deficient in the related to the antagonistic regulation of CDK1–cyclin B NF-κB activator iKKβ show reduced JNK phosphatase kinase activity by JNKs and p38 MAPKs71.
activity, which leads to sustained JNK1 activation and in addition to the crosstalk at the level of downstream increased liver carcinogenesis76. However, the high levels targets, there is evidence indicating that the p38 MAPK of JNK1 activity induced by p38α downregulation are not pathway can negatively regulate JNK activity in several sufficient to increase the sensitivity of hepatocytes to lPs contexts (FIG. 2). The first evidence for this crosstalk was or TNF-induced toxicity, unless NF-κB is also partially the observation that chemical inhibition of p38α and inhibited75. The increased lPs-induced liver damage p38β strongly increased the activation of JNK, which caused by simultaneous inhibition of the p38α and NF-κB was induced by il-1 and sorbitol in epithelial cel s and pathways correlates with reduced levels of the caspase 8 by lipopolysaccharides (lPs) in macrophages72. The inhibitor CFlAR75 (FIG. 2). JNK activation can also be nega- authors proposed that a negative feedback mecha- tively regulated by the NF-κB target gene Gadd45β, which nism exists that is mediated by p38α phosphorylation has been implicated in the regulation of TNF-induced cel of TAB1, a subunit of the kinase TAK1 (also known as death and liver regeneration77,78. These results il ustrate MAP3K7), which functions as a MAP3K upstream of how cell fate decisions are regulated in vivo by complex both p38 MAPKs and JNKs and also phosphorylates interactions between different signalling pathways that are inhibitor of nuclear factor kappa-B kinase subunit-β determinants for cancer development (FIG. 2).
(iKKβ), leading to nuclear factor kappa-B (NF-κB) acti- vation72 (FIG. 2). Recent work has proposed that p38α also Inflammation, migration and metastasis
negatively regulates the activity of MlK3 (also known as Chronic inflammation is a potent cancer promoter79,80, MAP3K11), another MAP3K upstream of JNK73.
and has been linked to increased cancer cell survival and increased activation of JNK on p38α inhibition has the induction of angiogenesis and invasion. Evidence also been observed in mouse models. For example, p38α- for the control of these processes by the JNK and p38 deficient myoblasts do not exit the cell cycle and prolif- MAPK pathways comes from the fact that these enzymes erate in differentiation-promoting conditions, which is regulate the activity and expression of key inflammatory accounted for by increased activation of the JNK/JuN mediators, including cytokines and proteases, which pathway64. This JNK hyperactivation correlates with affect cancer progression.
reduced levels of the MAPK phosphatase dual specificity protein phosphatase 1 (DusP1; also known as MKP1) Functions of JNKs. The JNK pathway has been linked to
in p38α-deficient myoblasts64 (FIG. 2). Fetal hemato poietic the expression of cytokines that control inflammation cel s and MEFs lacking p38α also show increased pro- and cancer, although to a lesser extent than p38 MAPKs4. liferation owing to sustained activation of the JNK/JuN The role of JNKs in liver inflammation and cancer has pathway. However, JuN-deficient hepatocytes show been studied using the TNFα-mediated concanavalin A increased p38α phosphorylation74, which is responsible mouse model (Con A mouse model) for acute hepatitis, for impaired proliferation after partial hepatectomy, sug- which involves T cel s and cytokines. During Con A- gesting that the JNK/JuN pathway can also affect p38 mediated hepatitis, binding of TNFα to its receptors MAPK activity. importantly, mice with a liver-specific results in JNK activation by a complex signal ing net- deletion of p38α are more susceptible to chemically work, which leads to the induction of AP1 and NF-κB. induced liver cancers, and JNK inactivation suppressed Con A-mediated hepatitis is prevented in mice that lack the increased proliferation of p38α-deficient hepatocytes JNK1 or JNK2 (REF. 81) and is probably mediated by an and tumour cel s42. The hyperactivation of the JNK/JuN iTCH–caspase 8–CFlAR pathway. in contrast to JNK, pathway in fetal hematopoietic cel s was proposed to be JuN mediates hepatocyte survival by transcription- Concanavalin A mouse mediated by the upregulation of the adaptor protein al y regulating the expression of inducible nitric oxide gRB2-related adaptor protein 2 (gRAP2), which in turn synthase (NOs2), controlling the subsequent release of This hepatitis model requires intravenous injection of the leads to the activation of the kinase HPK1 (also known nitric oxide and protecting the liver from hypoxia and lectin concanavalin A and is as MAP4K1) (FIG. 2). By contrast, JNK upregulation in oxidative stresses, which are events that are often linked dependent on T cells and p38α-deficient MEFs does not seem to involve gRAP2 to cancer82. interestingly, inhibition of NF-κB in a mouse inflammatory cytokines, such or HPK1, but correlates with increased phosphoryla- model of liver cancer results in sustained JNK activity, as TNFα. It recapitulates tion of MKK7 (REF. 42). Treatment of mice with lPs also increased cell death and cytokine-driven compensatory aspects of viral and autoimmune hepatitis in induces JNK hyperactivation in p38α-deficient livers, proliferation81,83, indicating that both JuN/AP1 and which does not seem to depend on JNK phosphatases, NF-κB functionally antagonize the death-promoting NATuRE REviEws CanCer
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2009 Macmillan Publishers Limited. All rights reserved functions of JNK. Recently, Con A-induced hepatitis Functions of p38 MAPKs. p38α regulates the induction
was shown not to be affected in mice that lacked both of the pro-inflammatory mediator cyclooxygenase 2 JNK1 and JNK2 in hepatocytes, although hepatitis (COX2), which could potential y contribute to cancer development was prevented when JNK1 and JNK2 were progression in non-melanoma skin cancer, breast can- deleted only in hematopoietic cel s84 (TABLE 1). it was pro- cer and gliomas88–90. in addition, p38α has a key role posed that TNFα production by myeloid cel s might be in the production of many cytokines, such as TNFα, important for JNK1 and JNK2 function, although the il-1 and il-6, which have pro-inflammatory, pro- liver damage measured by the levels of liver-specific survival and angiogenic effects91. p38α can regulate enzymes was 80–90% less than the levels published in cytokine expression by modulating transcription fac- other studies.
tors, such as NF-κB79, or at the post-transcriptional Recent work has linked the endoplasmic reticulum level, by regulating mRNA stability and protein trans- (ER) stress response to JNK activation in intestinal lation, which is thought to be mostly mediated by the inflammation, and possibly cancer progression. Mice downstream kinase MK2 (REF. 92). specific deletion of lacking the transcription factor XBP1 in intestinal epi- p38α in myeloid or epithelial cel s has provided in vivo thelial cel s develop spontaneous enteritis with increased evidence for the importance of this pathway in cytokine susceptibility to colitis and inflammatory bowel disease85. production and inflammatory responses93,94 (TABLE 1). By interestingly, XBP1 single nucleotide polymorphism contrast, p38β does not seem to be required for acute or variants have been associated with human inflamma- chronic inflammatory responses95,96.
tory bowel disease, suggesting that increased JNK sig- p38α may also directly affect tumour invasion and nalling might link cell-specific ER stress to the induction angiogenesis independently of its role in inflamma- of organ-specific inflammation and subsequent cancer tion. For example, p38α can induce expression of the development. Other inflammatory diseases proposed to matrix metalloproteinases MMP1, MMP3 and MMP13, be controlled by JNK signalling in mouse models are which regulate matrix remodelling and degradation by rheumatoid arthritis, in which JNK1 and JNK2 regulate metastatic cancer cel s, as well as vascular endothelial the expression of metalloproteinases and TNFα86, and growth factor A (vEgFA), a potent inducer of tumour atherosclerosis in which JNK2 is proposed to phospho- survival and angiogenesis21. in addition, p38α can acti- rylate scavenger receptor A87. The link between the vate hypoxia inducible factor 1 (HiF1), which has a key expression of JNK-dependent targets, such as metallo- role in hypoxia-driven expression of angiogenic factors, proteinases and inflammatory cytokines, and cancer at least partly through the stabilization of its α-subunit97. progression has yet to be established in mouse models Experiments that used cancer cell lines in various inva- of cancer and metastasis.
sion assays further support a role of p38α in metastasis. Table 1 Phenotypes of Jun N-terminal kinase and p38 mitogen-activated protein kinase knockout mice
MaPK
Disease and cancer model
Thin epidermis, T cell differentiation defects Hepatitis resistant (Con A) Liver cancer reduced (DEN) Skin cancer increased (DMBA and TPA) Gastric cancer reduced (MNU) Keratinocyte hyperplasia, Hepatitis resistant (Con A) T cell differentiation defects Liver cancer not affected Skin cancer reduced (DMBA and TPA) MAPK10– /– (JNK3) Resistance to excitotoxic neuronal cell death MAPK9–/– MAPK8 f/f × Alb-Cre Hepatitis — no effect (Con A) MAPK9–/– MAPK8 f/f × Mx-Cre Hepatitis resistant (Con A) MAPK9–/– MAPK8 f/f × Fabp4-Cre Fat phenotype Diabetes, hepatic insulin resistance MAPK14–/– (p38α) Placental defect, death by E12.5 MAPK14 f/f × More-Cre Postnatal death, hyperproliferation of fetal haematopoietic cells Not applicable MAPK14 f/f × RERTn-Cre Lung hyperplasia Lung cancer increased (KrasG12V) MAPK14 f/f × Alb-Cre; Mx-Cre Erythroid proliferation defects Liver cancer increased (DEN and Pb) MAPK14 f/f × MLC-2a-Cre Proliferation of adult cardiomyocytes MAPK14 f/f × Lys-Cre Reduced cytokine production MAPK14 f/f × K14-Cre; Lys-Cre Reduced inflammatory responses Skin injury (SDS and UVB) MAPK11–/– (p38b) MAPK12–/– (p38γ) Impaired insulin secretion and survival of pancreatic b-cells Skin cancer (DMBA and TPA) and lung cancer (KrasG12V) reduced Con A, concanavalin A; DEN, diethylnitrosamine; DMBA, 12-dimethylbenz(a)anthracene; f/f, flox/flox conditional allele; JNK, Jun N-terminal kinase; LPS, lipopolysaccharides; MAPK, mitogen-activated protein kinase; MNU, methyl-nitroso-urea; Pb, phenobarbital; SDS, sodium dodecyl sulphate; TPA, 12-O-tetradecanoylphorbol-13-acetate; UVB, ultraviolet B. 542 AugusT 2009 vOluME 9
2009 Macmillan Publishers Limited. All rights reserved For example, p38α activity is required for the invasive more susceptible to skin tumours, whereas papilloma capacity of human hepatocel ular carcinoma (HCC) and formation was found to be substantially reduced in head and neck squamous cell carcinoma cell lines98,99, JNK2-knockout mice115,116. These data imply an onco- and increased activation of p38α by MKK3 promotes gli- genic function for JNK2, whereas JNK1 seems to be a oma invasiveness both in cell-based assays in vitro and in suppressor of skin tumour development. At the molecu- rat brain slices ex vivo100. in addition, regulation of tumour lar level, it was suggested that differential regulation of cell extravasation by p38α has been proposed to account ERK and AKT signalling, as well as altered AP1 DNA for the reduced number of lung metastases observed on binding activities, could account for the specific func- intravenous injection of B16 or llC tumour cel s in p38α tions of JNK1 and JNK2 in skin tumours. whether these heterozygous versus wild-type mice101. p38δ has also differences are the molecular basis for the cell context- been proposed to regulate squamous cell carcinoma inva- dependent JNK phenotypes observed in skin versus liver sion99, and p38γ has been associated with Ras-induced needs to be investigated in future experiments.
invasion102. By contrast, the p38 MAPK activator MKK6 On the basis of studies of Apcmin mice and transgenic has been reported to suppress metastasis103 or to have no mice that specifical y express JNK in the intestine, JNK1 effect104, depending on the experimental model used.
and JuN have been proposed to be essential mediators of in addition to facilitating metastasis by the mecha- oncogenic β-catenin signalling in tumours of the smal nisms discussed above, p38α also regulates cancer intestine117,118. By contrast, chemical y induced colitis- cell migration105–109. MK2 has an important role in cel associated tumour formation was not affected by inac- migration downstream of p38α by remodelling the actin tivating JNK1 or JuN in intestinal epithelium and JuN cytoskeleton. This cytoskeletal remodelling may be medi- in myeloid cells119. Moreover, a study has shown that ated by the phosphorylation of heat shock 27 kDa protein JNK1-deficient mice spontaneously develop intestinal (HsP27), inducing its release from F-actin caps108, or by tumours120, although this finding could not be confirmed the activation of the protein kinase liMK1, which in turn by other laboratories. The exact role of JNK proteins in phosphorylates and inactivates the protein cofilin110.
intestinal tumorigenesis is not fully understood and requires further investigations using conditional alleles Mouse cancer models
of the respective genes.
genetical y engineered mouse models for components JNK activation has been detected in human gastric cancer of the JNK and p38 MAPK pathways, as well as car- samples and, consistent with this, JNK1 controls both cinogenesis studies in various organs, have provided tumour initiation and promotion by affecting cell prolif- new insights into the diverse and sometimes opposing eration and ROs production in a mouse model of gastric molecular functions of JNKs and p38 MAPKs (TABLE 1). cancer caused by methyl-nitroso-urea treatment121.
DEN–phenobarbital The leukaemia-associated BCR–ABl protein activates Functions of JNKs. The three JNK proteins can exert the JNK pathway in haematopoietic cells, leading to
A fully established and widely pro- and anti-oncogenic functions in different cell types increased AP1 transcriptional activity and inhibition of used model for liver cancer and stages of cancer development.
apoptosis. in addition, disruption of JNK1 inhibits trans- development in mice. In several studies only the carcinogen HCC is the third most common cause of death from formation of pre-B cel s in vitro and in vivo; this is partly DEN (diethylnitrosamine) is cancer in the world. several studies have demonstrated mediated by the expression of AKT and BCl2 (REF. 122), applied to young mice without a requirement for JuN in the development of HCC which is a signalling pathway that is also relevant in other tumour promotion, whereas through antagonizing the pro-apoptotic function of tumours and is amenable to targeted therapies.
the classical protocol depends p53 (REF. 111). similarly, JNK1 deficiency (but not JNK2 on two-stage carcinogenesis with DEN being applied as the deficiency) has been shown to significantly decrease Functions of p38 MAPKs. subcutaneous xenograft
initiator and phenobarbital as susceptibility to diethylnitrosamine (DEN)-induced experiments have shown that MEFs deficient in either the promoter of liver HCC formation112 (TABLE 1). Reduced HCC develop- p38α123 or the p38 MAPK activators MKK3 and MKK6 ment correlated with decreased expression of cyclin D (REF. 124) lead to a higher oncogene-induced tumour bur- DMBA–TPA protocol and vEgFA, as well as reduced hepatocyte proliferation and den in nude mice than their wild-type counterparts. The A widely applied and ful y neovascularization. These findings were recently function of p38α as a tumour suppressor in vivo has been established two-stage skin substantiated, both in mouse models and in human substantiated by studies that used genetical y modified carcinogenesis protocol that tumour cell lines, showing that impaired liver cel pro- mice. Protein phosphatase 1D also known as depends on tumour initiation liferation and tumour formation following JNK1 down- wiP1) transcription is stimulated by p53 and can target with DMBA (7,12-dimethylbenz(a)anthracene) regulation is caused by reduced expression of MYC and p38 MAPKs, among other substrates. genetic inactiva- and promotion with TPA increased expression of the CDK inhibitor p21 (REF. 113). tion of PPM1D reduces mammary gland tumorigenesis Pharmacological inhibition of JNKs with an inhibitory in mice that express the Erbb2 or Hras oncogenes, which peptide also reduced HCC development in both cancers are under the control of the mouse mammary tumour in mice induced by a DEN–phenobarbital protocol and in virus (MMTv) promoter. This correlates with increased Apcmin mice Mice carrying a mutation in the xenografted human HCC cel s, suggesting that JNK1 levels of p38 MAPK activity and apoptosis. importantly, Apc tumour suppressor gene, targeting should be considered as a new therapeutic a chemical inhibitor of p38α and p38β restores mam- which is thought to initiate approach for HCC treatment114.
mary tumour formation in PPM1D-deficient mice that intestinal tumorigenesis. The contribution of either JNK1 or JNK2 to tumour express MMTv-Erbb2 (REF. 125). Conversely, targeted Mutation of Apc leads to development was also investigated in mouse skin car- expression of PPM1D in the breast epithelium increases increased b-catenin-mediated transcription of proliferation- cinogenesis using the DMBA–TPA protocol. in contrast the sensitivity of mice to MMTv-ErbB2-induced mam- promoting genes. to liver cancer, JNK1-knockout mice seemed to be mary tumorigenesis, whereas the co-expression of a NATuRE REviEws CanCer
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2009 Macmillan Publishers Limited. All rights reserved constitutively active form of the p38 MAPK activator JNK and p38 MAPK pathways in human cancer
MKK6 in the mammary gland abolishes the effect of Altered expression of JNK and p38 MAPK proteins in PPM1D overexpression126. studies in mice deficient for human tumours and cancer cel lines is often observed, gADD45α, an activator of MEKK4 that functions as a although it is rarely known whether these proteins are MAP3K upstream of both p38 MAPKs and JNKs (FIG. 1), causal y involved in proliferation control and the devel- also support a tumour suppressor role for these path- opment of a specific tumour type. The best evidence for ways in breast cancer. Deletion of Gadd45α increases a role of these pathways in human cancer comes from MMTv-Ras-induced mammary tumour development, genetic studies identifying MKK4, a MAP2K that acti- which correlates with reduced levels of both apopto- vates both JNKs and p38α (FIG. 1), as a putative tumour sis and senescence, probably owing to the impaired suppressor. loss-of-function alleles were found in 5% of activation of JNK and p38 MAPKs, respectively127. human pancreatic, lung, breast, colon and prostate can- The activation of p38α has also been linked to liver cer, although there is also evidence from in vitro studies cell apoptosis in mouse models that either overexpress that MKK4 can promote tumorigenesis133,134. The emerg- the TgFβ signal transducer Smad3 (REF. 128) or have ing views on how these pathways might affect human impaired ATF2 transcriptional activity129.
cancers, as well as evidence from human genetic studies, More direct evidence for the negative regulation of are discussed below and are summarized in TABLE 2.
tumorigenesis by p38 MAPKs in mice has been pro- vided by studies that used conditional p38α alleles JNKs and human cancer. large-scale sequencing analyses
(TABLE 1). p38α-deficient mice are sensitized to Kras-
of protein kinases in human tumours have identified induced lung tumorigenesis, which has been attributed somatic mutations in the JNK pathway, that presumably to the immature and hyperproliferative lung epithe- activate JNK1, JNK2 and the upstream kinase MKK7 lium that results from p38α inactivation43. in addition, (REFs 135,136). These data suggest that mutations in the hepatocyte-specific deletion of p38α promotes chemi- JNK pathway can be involved in cancer development.
cal y induced liver cancer, for which upregulation of the As in rodent model systems, in many human can- JNK/JuN pathway plays an important part in increased cers, JNKs can exert dual functions, either oncogenic proliferation of p38α-deficient tumour cel s42. A recent or tumour suppressive. in HCC, JNK1 seems to be report has shown that p38α suppresses ROs accumula- oncogenic, as increased kinase activity and prolifera- tion and cell death in hepatocytes, and it was proposed tion of tumour cel s are correlated with an increase in that the release of il-1α by necrotic hepatocytes may tumours113 (TABLE 2). Moreover, sustained JNK1 activa- indirectly contribute to liver carcinogenesis by stimulat- tion was found to be associated with altered histone ing carcinogen-induced compensatory proliferation130. H3 methylation in human HCCs137. interestingly, as However, mice that lack p38δ show reduced susceptibil- for MKK4, JNKs are also mutated in cancer and the ity to the development of both skin carcinomas induced loss of JNK3 function promotes tumour formation. For by DBMA and TPA treatment and Kras-induced lung example, (which encodes JNK3) might be a tumours, suggesting that p38δ positively regulates putative tumour suppressor gene, as mutations were found in 10 of 19 human brain tumours examined138.
Finally, deletion of the protein kinase MK5 (also The role of JNKs in prostate cancer development is known as PRAK or MAPK5) increases skin carcino- of particular interest, because this cancer is one of the genesis induced by DBMA in the absence of any tumour most common neoplasms in ageing males and is a seri- promoter, and also accelerates the lymphomagenesis ous health problem. The tumour suppressor PTEN is the induced by the expression of an Eμ-NRasG12D trans- second most commonly mutated tumour suppressor in gene131. These results suggest that MK5 may act as a human cancers and is frequently lost in prostate cancer. tumour suppressor; its function is probably mediated PTEN loss leads to AKT activation and increased JNK by the regulation of oncogene-induced senescence, activity in various human cancer cell lines and human although the extent of the p38 MAPK contribution clinical prostate cancer samples139. gene expression anal- to MK5 activation is controversial132. Therefore, more yses were used to show that several members of the JNK mechanistic studies are required to define the functions pathway were upregulated in prostate cancer140, whereas of p38 MAPKs, their regulators and targets in mouse JuNB was identified as an inhibitor of prostate carcino- models of cancer.
genesis141. Furthermore, PTEN deficiency sensitizes Table 2 Role of Jun N-terminal kinases and p38 mitogen-activated protein kinases in human cancer
Human cancer
Liver cancer (hepatocellular carcinoma) JNK1 highly activated p38α activity downregulated JNK3 loss-of-function mutations Lymphoma, glioma, lung, thyroid, breast, head and neck p38α activity upregulated squamous cell carcinomas JNK, Jun N-terminal kinase; MAPK, mitogen-activated protein kinase.
544 AugusT 2009 vOluME 9
2009 Macmillan Publishers Limited. All rights reserved Table 3 Inhibitors of Jun N-terminal kinases and p38 mitogen-activated protein kinases in clinical trials
Compound
Phase I: fibrotic diseases, inflammatory disease Celgene Corporation Phase I/II: myelogenous leukemia (discontinued) Celgene Corporation Phase II: Crohn's disease, cancer, HIV, Cytokine PharmaSci inflammatory disease XG-102 (D-JNKI-1) Phase II: stroke, Alzheimer's disease (TAT-coupled peptide)Talmapimod Phase I/II: multiple myeloma, myelodysplastic Phase II: rheumatoid arthritis Phase I/II: rheumatoid arthritis, neuropathic pain Phase I: haematological cancers Phase I/II: dental inflammatory pain, cancer Phase II: arthritis, pain JNK, Jun N-terminal kinase; MAPK, mitogen-activated protein kinase.
cel s to JNK inhibition and therefore JNKs can be seen p38 MAPK and JNK as drug targets
as crucial components of the PTEN–Pi3K pathway The key roles of p38α in the production of pro-inflammatory and as potential therapeutic targets.
cytokines and in the signal relay from cytokine recep- Recently, analysis of Drosophila melanogaster seg- tors have led to the development of a large number of mentation networks identified the E3 ubiquitin ligase small-molecule p38 MAPK inhibitors (TABLE 3). Many complex factor sPOP as an important regulator of JNK of these have shown high specificity towards p38α activity, which seems to be conserved in TNF-mediated in vitro and have yielded promising results in preclini- JNK signalling. Moreover, sPOP was found to be over- cal studies for inflammatory diseases, but few have expressed in 99% of clear cell renal carcinomas, the most progressed beyond Phase i clinical trials, mostly owing prevalent form of kidney cancer142. This study il ustrates to side effects, such as liver toxicity91,150. However, it is the power of the use of genetic studies for the identification unclear whether the side effects are due to p38 MAPK of new cancer genes.
inhibition or to the drugs that act on additional targets. A new generation of more selective p38 MAPK inhibi- p38 MAPKs and human cancer. in support of the tumour tors is currently being developed that seem to have less
suppressor function of p38α, several negative regulators toxic effects in animal models. An important considera- of p38 MAPK signalling have been found to be overex- tion, given the evidence in support of p38α as a tumour pressed in human tumours and cancer cell lines, including suppressor20,21, is whether inhibition of p38α might result the phosphatases PPM1D and DusP26 (REFs 123,143,144) in an increased predisposition to cancer. This possibility and the inhibitors of the MAP3K apoptosis signal- was supported by experiments in mouse models of lung regulating kinase 1 (AsK1), glutathione S-transferase Mu 1 and liver cancer42,43. However, chronic inflammation (gsTM1) and gsTM2 (REF. 52). large-scale sequencing is a potent cancer promotor and cytokines are impor- has also identified somatic mutations in the p38 MAPK tant survival factors for cancer cel s79,80, suggesting that pathway in a small number of human tumours135, but p38α inhibition might be beneficial for the treatment of the importance of these mutations remains to be inves- inflammation-associated cancers, such as colon cancer tigated. interestingly, some human tumours, such as and possibly HCC.
HCCs, have lower p38 MAPK and MKK6 activity than The p38α inhibitors may also be useful to treat non-tumorigenic tissues (TABLE 2), supporting the obser- tumours that rely on p38 MAPK activity for progres- vation that increased p38 MAPK activity induces apop- sion, or could be combined with DNA-damaging tosis in hepatoma cell lines145. However, increased levels chemotherapy to trigger cancer cell death by impair- of phosphorylated p38α have been correlated with malig- ing p38α-mediated cell cycle arrest and DNA repair nancy in various cancers, including follicular lymphoma, mechanisms100,151. in addition, p38 MAPK inhibition lung, thyroid and breast carcinomas, as well as glioma may increase the sensitivity of cancer cel s to the effect and head and neck squamous cell carcinomas99,100,146–149 of chemotherapeutic drugs that usually act on divid-(TABLE 2). These observations are consistent with the idea ing cel s. For example, quiescent leukaemic cel s treated that, depending on the type of cancer and tumour stage, with a p38 MAPK inhibitor proliferate and become sensi- cancer cel s with pro-tumorigenic mutations in the p38 tive to the effect of the anti-mitotic drug 5-fluorouracil152. MAPK pathway have a selective advantage.
As a note of caution, combination therapies should in summary, these data imply that inhibition of the take into account that many chemotherapeutic drugs JNK and p38 MAPK pathways for therapeutic purposes require a functional p38α pathway for efficient action153. should be strictly dependent on cell context, tumour cel Final y, drug-induced activation of p38α, for example type and tumour stage.
by inhibiting phosphatases, could be a strategy worth NATuRE REviEws CanCer
vOluME 9 AugusT 2009 545
2009 Macmillan Publishers Limited. All rights reserved exploring for sensitizing cancer cel s to apoptotic death. Another lesson learned from analysing mouse models However, this might induce an inflammatory response is the existence of crosstalk between the MAPK signal- as a side effect, which results in increased angiogenesis ling pathways in different cell types and stages of can- and invasion. given the many tumorigenesis-related cers. given the complexity of the underlying molecular functions that p38α can control, both in the cancer mechanisms, inhibiting these pathways is a big challenge, cell and in the tumour microenvironment, it is impor- which should nevertheless be undertaken with selective tant to carefully consider both the type and tumour drugs. whether targeting particular JNK and p38 MAPK stage before attempting to modulate p38α activity for genes or isoforms will be more beneficial than targeting cancer therapy.
the whole pathway must be considered. Moreover, com- The diverse functions of JNKs on cell proliferation bination therapies are likely to be important in the future, and on the induction of cell death are also being explored although deciding which drugs should be combined is not for targeted therapies that use both peptide inhibitors trivial. it is therefore essential to mechanistical y under- and small molecules154. Many of the above considera- stand the functions of MAPK family members in different tions for p38α also apply to JNK-dependent targeted tumour types and how the interplay between them and therapies. several companies have JNK inhibitors with interactions with other signalling pathways are wired.
different core structures at different stages of develop- genomic and proteomic strategies will certainly iden- ment (TABLE 3). Many inhibitors, such as sP-600125, tify new MAPK substrates and regulators, whereas molec- lack specificity and selectivity for the different JNK ular signatures obtained from sequencing and array data isoforms155, although a recent report describes a JNK1- in response to drug treatments should lead to the identi- specific inhibitor156. However, several peptide inhibitors fication of both new biomarkers and potential targets for have been developed, such as JNKi1 (REF. 157), which has therapies. However, which targets will be clinical y relevant been successful y used in mouse models, for example, for and allow the eventual treatment of cancer patients? To HCC113, or Bi-78D3, which inhibits JNK activity through better validate these targets, human transplantation and interfering with binding to the JNK-interacting protein 1 mouse tumour models are essential. Mouse genetic stud- (JiP1) scaffold158. As the field of JNK inhibitors is rapidly ies are time-consuming and human xenografts are rightly moving, it is anticipated that several targeted therapies considered artificial. However, mouse cancer models are with new drugs will be successful y applied and used in continuously evolving to better resemble the pathogen- the clinic in the near future.
esis of human cancer and although they are demanding, both in terms of time and resources, they provide valu- Conclusions and perspectives
able information in addition to ex vivo experiments with will future therapeutic strategies depend on new mouse cultured cel s. One alternative experimental strategy is the models and human genetic studies? One of the lessons treatment of freshly dispersed primary tumours with new learned from mouse genetic studies is that specific drugs, followed by transplantation into immune-deficient side effects can be observed by targeting JNKs and p38 mice, which provides a rapid initial efficacy test.
MAPKs. For example, the increased lung tumori genesis The final goals of studies using mouse models and observed in p38α knockout mice strongly suggests that human genetic and pharmacological approaches are to p38α inhibitors should not be given to people with an better define the specific roles of MAPK signalling in increased risk of developing lung cancer. similarly, specific tumours. in addition to angiogenesis, future the increased liver cancer development in p38α-deficient therapies should target the microenvironment and other mice should also be considered. These studies, as wel non-tumorigenic cel s, such as macrophages and stromal as the analysis of human cell lines and tumours, should cel s. we are convinced that promising new avenues for provide important information on which types of cancer the treatment of cancer are on the horizon, which wil are likely to respond to therapies targeted against JNKs undoubtedly lead to better, more efficient and faster and p38 MAPKs.
therapies in the years to come.
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grants from the Spanish Ministerio de Ciencia e Innovación all linKS are aCtive in tHe online PDf
(MICINN) (BFU2007-60575), Fundación La Caixa, MICINN/ NATuRE REviEws CanCer
vOluME 9 AugusT 2009 549
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