Inhibition of p38 MAPK sensitizes tumour cells to cisplatin‐induced apoptosis mediated by reactive oxygen species and JNK

• Published in: EMBO molecular medicine 2013-11, Vol.5 (11), p.1759-1774
• Main Authors: Pereira, Lorena, Igea, Ana, Canovas, Begoña, Dolado, Ignacio, Nebreda, Angel R.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Breast cancer; Cancer therapies; Cell cycle; Cell Line, Tumor; Chemotherapy; Cisplatin; Cisplatin - administration & dosage; Colorectal cancer; Deoxyribonucleic acid; Design; DNA; Epithelial cells; Experiments; Female; Genetic transformation; Humans; JNK; Kinases; Malignancy; MAP kinase; MAP Kinase Kinase 4 - genetics; MAP Kinase Kinase 4 - metabolism; Medical prognosis; Mice; Mice, Transgenic; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - physiopathology; p38 MAPK; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; Research Article; ROS; Signal transduction; Signal Transduction - drug effects; Tumors
• ISSN: 1757-4676; 1757-4684
• DOI: 10.1002/emmm.201302732

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. Graphical Abstract p38alpha/beta inhibition is shown here to sensitize tumor cells to cisplatin‐induced apoptosis by increasing ROS levels and activating the JNK pathway, providing an interesting therapeutic strategy of combining p38 inhibitors to anti‐cancer drugs.