Regulation of cancer cell viability by p38 MAPK

Resum

Regulation of the redox state is essential to maintain cellular homeostasis. In fact, dysregulated reactive oxygen species (ROS) production has been associated with enhanced tumorigenicity in epithelial cells. However, the pro-tumorigenic effect of the accumulation of ROS can turn out to be a double-edged sword, since high levels of these species may lower the apoptotic threshold for cytotoxicity. Therefore, redox regulation plays an important role in tumor cell survival. The p38¿ protein kinase is an important regulator of many cellular responses. It is well established that p38¿ signaling negatively regulates epithelial cell transformation, but enhanced p38¿ kinase activity has been also correlated with bad clinical prognosis in some tumor types. This, together with the fact that p38¿ has been implicated in the proliferation of some cancer cell lines, led us to hypothesize that this protein kinase could be a good target for cancer therapy. We performed a screening to try to identify synthetic lethal partners of p38¿, but we only found one potential candidate. We also investigated the role of p38¿ in the response of tumor cells to chemotherapeutic agents that induce DNA damage. Our results provide genetic and pharmacological evidence showing that inhibition of p38¿ cooperates with the chemotherapeutic agent cisplatin to kill tumor cells. We show that p38¿ inhibition results in ROS upregulation, which in turn activates the JNK pathway via inactivation of phosphatases, sensitizing human tumor cells to cisplatin-induced apoptosis. Using a mouse model for breast cancer, we also show that inhibition of p38¿ cooperates with cisplatin treatment to reduce tumor size and malignancy in vivo. Taken together, our results illustrate a new function of p38¿ that helps tumor cells to survive chemotherapeutic drug treatments by inducing the expression of antioxidant enzymes, and reveal that the combination of p38¿ inhibitors with cisplatin can be potentially exploited for cancer therapy. KEYWORDS: p38 MAPK ROS JNK cancer apoptosis redox signaling chemotherapy cisplatin phosphatases