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World J Gastroenterol. Aug 7, 2014; 20(29): 9744-9758
Published online Aug 7, 2014. doi: 10.3748/wjg.v20.i29.9744
p38α MAPK pathway: A key factor in colorectal cancer therapy and chemoresistance
Valentina Grossi, Alessia Peserico, Tugsan Tezil, Cristiano Simone
Valentina Grossi, Alessia Peserico, Tugsan Tezil, Cristiano Simone, Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari “Aldo Moro”, 70124 Bari, Italy
Valentina Grossi, Alessia Peserico, Tugsan Tezil, Cristiano Simone, National Cancer Institute, IRCCS Oncologico Giovanni Paolo II, 70124 Bari, Italy
Alessia Peserico, Fondazione Mario Negri Sud, Santa Maria Imbaro 66030 (CH), Italy
Author contributions: All authors contributed to the manuscript.
Supported by Italian Association for Cancer Research (AIRC) fellowship (to Grossi V); Italian Foundation for Cancer Research (FIRC) fellowships (to Peserico A and Tezil T); Investigator Grant 2010 No. IG10177 to Simone C from the Italian Association for Cancer Research (AIRC) and by FIRB “Futuro in Ricerca” RBFR12VP3Q_003 (to Simone C) from the Italian MIUR
Correspondence to: Cristiano Simone, MD, PhD, Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari “Aldo Moro”, Via Nazionale 8/A, Bari 70124, Italy.
Telephone: +39-87-2570210  Fax: +39-87-2570299
Received: November 5, 2013
Revised: March 13, 2014
Accepted: May 19, 2014
Published online: August 7, 2014

Colorectal cancer (CRC) remains one of the most common malignancies in the world. Although surgical resection combined with adjuvant therapy is effective at the early stages of the disease, resistance to conventional therapies is frequently observed in advanced stages, where treatments become ineffective. Resistance to cisplatin, irinotecan and 5-fluorouracil chemotherapy has been shown to involve mitogen-activated protein kinase (MAPK) signaling and recent studies identified p38α MAPK as a mediator of resistance to various agents in CRC patients. Studies published in the last decade showed a dual role for the p38α pathway in mammals. Its role as a negative regulator of proliferation has been reported in both normal (including cardiomyocytes, hepatocytes, fibroblasts, hematopoietic and lung cells) and cancer cells (colon, prostate, breast, lung tumor cells). This function is mediated by the negative regulation of cell cycle progression and the transduction of some apoptotic stimuli. However, despite its anti-proliferative and tumor suppressor activity in some tissues, the p38α pathway may also acquire an oncogenic role involving cancer related-processes such as cell metabolism, invasion, inflammation and angiogenesis. In this review, we summarize current knowledge about the predominant role of the p38α MAPK pathway in CRC development and chemoresistance. In our view, this might help establish the therapeutic potential of the targeted manipulation of this pathway in clinical settings.

Keywords: p38 mitogen-activated protein kinase, Chemoresistance, Molecularly-targeted drugs, Colorectal cancer, Cell death

Core tip: The pro-apoptotic effects of p38α activation are long recognized; however, a significant number of reports describes the involvement of p38α in cancer-specific metabolism, survival, proliferation, and chemoresistance of colorectal cancer cells and tissues. p38α blockade exerts its chemosensitizing effects through nuclear accumulation of FoxO3A and activation of its pro-apoptotic gene expression program, thereby improving the efficacy of anti-cancer treatments. Apoptosis induction upon p38α inhibition requires Bax, which may thus serve as a predictive bio-marker for p38α-targeted therapy response. The novel role described for the p38-FoxO3A axis in chemoresistance might offer new options for combined therapies and personalized medicine approaches.