Signalling : DNA damage is Stressful

DNA damage activates a complex signalling network that functions to mediate DNA repair and activate cell-cycle checkpoints. Michael Yaffe and colleagues now show that p53-deficient tumour cells rely on an alternative, parallel signalling pathway to activate cell-cycle checkpoints after treatment with DNA-damaging anticancer drugs.

DNA-damage checkpoints are primarily activated by ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia mutated and Rad3-related (ATR) kinases, predominantly through the activation of the mediator kinases CHK2 and CHK1, respectively. Previous data indicated that another mediator kinase, mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2), which is a downstream kinase of the p38 MAPK, also functions in checkpoint activation in response to cellular stress, such as heat shock and UV irradiation. Therefore, Yaffe and colleagues investigated whether p38 and MAPKAPK2 are part of the DNA-damage signalling network.

The authors showed that the treatment of cells with the anticancer agents cisplatin, camptothecin and doxorubicin increased the activating phosphorylation of p38 and MAPKAPK2. Furthermore, the p38-dependent phosphorylation of MAPKAPK2 occurred downstream of ATR in response to cisplatin and camptothecin, and downstream of ATR and ATM in response to doxorubicin. A major effector of DNA-damage checkpoint activation is p53. The authors showed that the p38–MAPKAPK2 arm of the DNA-damage response pathway was required for the survival of mouse embryonic fibroblasts (MEFs) after treatment with doxorubicin or cisplatin only when p53 was not present. Moreover, they showed that MAPKAPK2 is required for the activation of the G2/M and intra-S phase checkpoints in Trp53-/- MEFs after treatment with doxorubicin and cisplatin. In this context, MAPKAPK2 was required for checkpoint activation upstream of cell division cycle 25A and B (CDC25A and CDC25, despite the ATR-dependent activation of CHK1 in a parallel pathway.

So, given that most tumour cells are p53-deficient, could MAPKAPK2 be a clinically relevant anticancer target? The authors injected HRASV12-transformed Trp53-/- MEFs in which MAPKAPK2 was downregulated by short hairpin RNA into nude mice. The MAPKAPK2-deficient tumours that developed were slightly larger than controls but showed a dramatic decrease in size and weight when doxorubicin or cisplatin was administered, indicating that MAPKAPK2 inhibition might sensitize tumours to DNA-damaging agents. In addition, they showed that UCN01, a CHK1 and CHK2 small-molecule inhibitor that is currently in clinical trials, also inhibits MAPKAPK2 at a similar concentration to CHK1 (CHK2 inhibition requires higher concentrations of the drug).

Therefore, the simultaneous inhibition of CHK1 and MAPKAPK2 might account for the tumour sensitization effects of UCN01 that prompted the clinical trials. It remains unclear how and why ATR- and ATM-dependent checkpoint activation operates through p38–MAPKAPK2, CHK1 and CHK2. Because the MAPKAPK2-dependency is only apparent when p53 is not present and, unlike CHK1, MAPKAPK2 is not essential, the development of specific MAPKAPK2 inhibitors could be a viable approach to sensitizing cancer cells to DNA-damaging agents.