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Review
. 2014 Jan;171(1):24-37.
doi: 10.1111/bph.12432.

JNK signalling in cancer: in need of new, smarter therapeutic targets (V体育安卓版)

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Review

JNK signalling in cancer: in need of new, smarter therapeutic targets

Concetta Bubici et al. Br J Pharmacol. 2014 Jan.

Abstract

The JNKs are master protein kinases that regulate many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival and death. It is increasingly apparent that persistent activation of JNKs is involved in cancer development and progression. Therefore, JNKs represent attractive targets for therapeutic intervention with small molecule kinase inhibitors VSports手机版. However, evidence supportive of a tumour suppressor role for the JNK proteins has also been documented. Recent studies showed that the two major JNK proteins, JNK1 and JNK2, have distinct or even opposing functions in different types of cancer. As such, close consideration of which JNK proteins are beneficial targets and, more importantly, what effect small molecule inhibitors of JNKs have on physiological processes, are essential. A number of ATP-competitive and ATP-non-competitive JNK inhibitors have been developed, but have several limitations such as a lack of specificity and cellular toxicity. In this review, we summarize the accumulating evidence supporting a role for the JNK proteins in the pathogenesis of different solid and haematological malignancies, and discuss many challenges and scientific opportunities in the targeting of JNKs in cancer. .

Keywords: JNK1; JNK2; PARP14; apoptosis; cancer targets; hepatocellular carcinoma; multiple myeloma; survival V体育安卓版. .

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Figures

Figure 1
Figure 1
Schematic representation of the JNK signalling cascade. Like all other MAPK, the JNK signalling cascade consists of a three-component module of upstream MAP3Ks that couples the signals from the cell surface to intracellular protein effectors. Different MAP3Ks have been implicated in the JNK cascade, depending on the type of stimulus the cell receives. Once activated, MAP3Ks phosphorylate and activate components of the MAP2K module, such as MKK4 and MKK7, which in turn phosphorylate and stimulate the activity of distinct JNK isoforms through dual phosphorylation on threonine and tyrosine residues within a conserved Thr-X-Tyr motif. Upon activation, each JNK protein itself can phosphorylate serine and threonine residues on specific substrates, delivering different cellular activities.
Figure 2
Figure 2
JNKs regulate key cellular activities involved in cancer. JNKs are activated in response to different extracellular and intracellular stimuli, such as oncogenes, dietary agents, obesity, alcohol, infectious agents and irradiation. Persistent activation of JNKs affect tumourigenesis by both transcription-dependent and transcription-independent mechanisms involved in cell proliferation, survival, transformation, inflammation, migration and suppression of cell death.
Figure 3
Figure 3
Specific cellular targets of JNK1 and JNK2 in different types of cancer. A diagram showing the different targets regulated by the individual JNK proteins. Distinct functions of JNK1 and JNK2 in various cancers appear through differing regulation of specific substrates and/or downstream effectors. The development of inhibitors that target specific downstream effectors of the individual JNK proteins would provide unique opportunities for therapeutic interventions.

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