Role of Jun and Jun kinase in resistance of cancer cells to therapy

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Abstract

A series of kinases, the mitogen-activated protein (MAP) kinases, serves to regulate cellular responses to various environmental influences in metazoans. Three major pathways have been described, each with some overlap in substrate specificity that causes activation of parallel pathways. The activation of one of these, the Jun kinase pathway, has been implicated in apoptotic responses to DNA damage, cell stress and cytotoxic drugs. Under most circumstances in non-malignant cells it appears that c-Jun N-terminal kinase (JNK) activation is a pro-apoptotic event that results in turn in activation of pro-apoptotic members of Bcl-2 family and cytochrome c release from mitochondria. In cells with dysregulated/mutated proliferation or cell cycle controls, the role of JNK and of c-Jun is more controversial. We distinguish between the transcriptional effects of JNK and other protein interactions in which it participates. The initiation of mitochondrial apoptosis pathways by JNK is independent of its transcriptional effects for the most part. In certain cell types, c-Jun overexpression is clearly a basis for resistance to DNA-damaging drugs, and resistance reversal has been observed using c-jun antisense. This preliminary evidence suggests that c-jun may have a role in drug resistance, but additional work with patient tumor samples is required to validate the potential of the JNK pathway as a target.

Introduction

The kinase cascade that spans the signaling of stimuli at the membrane to nuclear responses is designated as the mitogen-activated protein (MAP) kinase pathway. The MAP kinases consist of at least four inter-related cytoplasmic signaling sequences that ultimately stimulate gene expression through activation of transcription factors (Johnson and Lapadat, 2002). These pathways transmit signals for proliferation, differentiation, apoptosis, DNA damage and general stress responses (Ptashne and Gann, 2003). The mapping of patterns of responses has been explored as a means of determining the activity of components of the pathways (Park et al., 2003). While the role of these pathways in responses to anticancer drugs is well documented, some of the experimental findings are conflicting and contradictory (Fan and Chambers, 2001). Nevertheless, a wealth of evidence implicates one of these pathways, the c-Jun N-terminal kinase (JNK) pathway, in apoptosis and response to cytotoxic drugs. Evidence particularly supports its involvement in the response and resistance to DNA-damaging agents such as cisplatin, and antimicrotubular agents such as taxanes. In this review we will summarize data that implicate these pathways in drug resistance and point to studies that may support a role for elements of these pathways as targets to sensitize cells to anticancer agents.

Section snippets

Mitogen-activated protein kinases

This series of kinases (Fig. 1) links membrane and intracellular sources of signals with their nuclear targets and consist of the subfamilies of extracellular signal-regulated kinase (ERK1 and ERK2), c-Jun N-terminal kinase (JNK1, JNK2 and JNK3) and p38 kinase (α, β, γ and δ) (Chang and Karin, 2001). Another MAPK, ERK5, has also been described as a mediator of Src activation (Zhou et al., 1995). By convention the serine-threonine kinases that transmit the signals through phosphorylation

Role of JNK and c-Jun in stress response and apoptosis

The JNK branch of the MAP kinase pathway is stimulated by multiple factors including cytokines (TNF, IL-1, other interleukins), DNA-damaging agents (drugs and radiation), environmental stresses (hypoxia, glucose deprivation), and in development, various signals for embryonic maturation (Weston and Davis, 2002). As befits this wide range of inputs, the outputs are similarly varied and sometimes contradictory (Leppa and Bohmann, 1999). Thus the stimuli result in modification of physiological

Evidence of JNK and c-Jun involvement in response to cytotoxic drugs

Apoptosis induced by DNA-damaging drugs, cisplatin in particular, can be presented as a sequence of events leading to cell death: during the initial step cisplatin binds to DNA (Brabec and Kasparkova, 2002) and the lesions formed cause the induction of signaling pathways leading either to damage repair (cell cycle arrest and induction of repair machinery) or commitment to apoptosis. The initiation of apoptosis involves activation of caspase 8 and/or release of cytochrome c from mitochondria and

Implications for cancer therapy

The model for signaling through JNK becomes increasingly complex as evidence mounts for crosstalk among the various signaling pathways that converge in its activation. The bulk of evidence favors a pro-apoptotic role for JNK under most circumstances (Davis, 2000). An important caveat to that conclusion is that most of the research has been done in non-malignant cells, and the genetic abnormalities that characterize a particular cancer may impose unpredictable functions. However, in development,

Clinical implications

The physiological role of JNK in the mature cell is unclear. A major role in apoptosis is unquestionable though, and at least in fibroblasts the axis of JNK to Bax/Bak to cytochrome c release and apoptosis has been carefully worked out (Lei et al., 2002). The issue is whether there are alternative or opposing responses in cells with genetic abnormalities that characterize cancer, and if so, whether these may provide a useful target in those tumors. So the first order of business would seem to

Conclusions and future directions

In conclusion, the JNK pathway has a central role in mediating cell death from some cytotoxic drugs. For c-Jun, the data are consistent: targeting c-Jun in resistant cells potentiates the action of cisplatin. For JNK, the bulk of the data support a pro-apoptotic role, recently shown to be exerted through an interaction with Bax and Bak. Unresolved is the basis through which one protein becomes a more important substrate than the other, if that is the fulcrum around which a decision to undergo

Acknowledgements

The studies in the authors’ laboratory were supported in part by CA 49820 from the NIH.

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