Open AccessInhibition of p38 MAPK sensitizes tumour cells to cisplatin‐induced apoptosis mediated by reactive oxygen species and JNK
Author(s) -
Pereira Lorena,
Igea Ana,
Canovas Begoña,
Dolado Ignacio,
Nebreda Angel R.
Publication year - 2013
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201302732
Subject(s) - cisplatin , mapk/erk pathway , p38 mitogen activated protein kinases , cancer research , apoptosis , downregulation and upregulation , cancer cell , microbiology and biotechnology , in vivo , chemistry , biology , cancer , signal transduction , chemotherapy , biochemistry , genetics , gene
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.