title: Inhibition of p38 MAPK sensitizes tumour cells to cisplatin-induced apoptosis mediated by reactive oxygen species and JNK.
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.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Lorena
authors.initials: L
authors.lastname: Pereira
authors.forename: Ana
authors.initials: A
authors.lastname: Igea
authors.forename: Begoña
authors.initials: B
authors.lastname: Canovas
authors.forename: Ignacio
authors.initials: I
authors.lastname: Dolado
authors.forename: Angel R
authors.initials: AR
authors.lastname: Nebreda
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D002945:Cisplatin
keywords: JNK; ROS; apoptosis; cisplatin; p38 MAPK