Inhibition of P38 MAPK Sensitizes Tumour Cells to Cisplatin-induced Apoptosis Mediated by Reactive Oxygen Species and JNK

Overview

Journal EMBO Mol Med

Specialty Molecular Biology

Date 2013 Oct 12

PMID 24115572

Citations 72

Authors

Lorena Pereira

Ana Igea

Begona Canovas

Ignacio Dolado

Angel R Nebreda

Affiliations

Soon will be listed here.

Abstract

The p38 MAPK pathway is an important regulator of many cellular responses. It is well established that p38 MAPK signalling negatively regulates epithelial cell transformation, but enhanced p38 MAPK activity has been also correlated with bad clinical prognosis in some tumour types. Here, we provide genetic and pharmacological evidence showing that p38 MAPK inhibition cooperates with the chemotherapeutic agent cisplatin to kill tumour cells. We show that p38 MAPK inhibition results in ROS upregulation, which in turn activates the JNK pathway via inactivation of phosphatases, sensitizing human tumour cells to cisplatin-induced apoptosis. Using a mouse model for breast cancer, we confirm that inhibition of p38 MAPK cooperates with cisplatin treatment to reduce tumour size and malignancy in vivo. Taken together, our results illustrate a new function of p38 MAPK that helps tumour cells to survive chemotherapeutic drug treatments, and reveal that the combination of p38 MAPK inhibitors with cisplatin can be potentially exploited for cancer therapy.

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