Journal
EMBO MOLECULAR MEDICINE
Volume 5, Issue 11, Pages 1759-1774Publisher
WILEY
DOI: 10.1002/emmm.201302732
Keywords
apoptosis; cisplatin; JNK; p38 MAPK; ROS
Categories
Funding
- Fundacion BBVA
- Spanish Ministerio de Ciencia e Innovacion [BFU2010-17850]
- European Commission FP7 'INFLA-CARE' [223151]
- Instituto de Salud Carlos III [FI08/00455]
- ICREA Funding Source: Custom
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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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