A novel cell type-specific role of p38α in the control of autophagy and cell death in colorectal cancer cells

Abstract

Cancer develops when molecular pathways that control the fine balance between proliferation, differentiation, autophagy and cell death undergo genetic deregulation. The prospects for further substantial advances in the management of colorectal cancer reside in a systematic genetic and functional dissection of these pathways in tumor cells. In an effort to evaluate the impact of p38 signaling on colorectal cancer cell fate, we treated HT29, Caco2, Hct116, LS174T and SW480 cell lines with the inhibitor SB202190 specific for p38a/b kinases. We report that p38a is required for colorectal cancer cell homeostasis as the inhibition of its kinase function by pharmacological blockade or genetic inactivation causes cell cycle arrest, autophagy and cell death in a cell type-specific manner. Deficiency of p38a activity induces a tissue-restricted upregulation of the GABARAP gene, an essential component of autophagic vacuoles and autophagosomes, whereas simultaneous inhibition of autophagy significantly increases cell death by triggering apoptosis. These data identify p38a as a central mediator of colorectal cancer cell homeostasis and establish a rationale for the evaluation of the pharmacological manipulation of the p38a pathway in the treatment of colorectal cancer. Colorectal cancer is a major health concern, with more than 1 000 000 new cases and 500 000 deaths expected worldwide per year.1 Prognostic evaluation is currently based on histological appearance, and there are no molecular markers internationally recognized as standard predictor factors. The conventional therapy involving surgery and adjuvant therapy seems to give rise to improvements in progression-free and overall survival. Nevertheless about 50% of patients die within 5 years owing to metastasis or recurrent disease.2 The prospects for further substantial advances in the management of colorectal cancer reside in a systematic genetic and functional dissection of cell cycle and cell death regulatory pathways in tumor cells in order to identify differential cellular effects of agents that may have a direct impact on cancer therapy.During the last decade, a number of deacetylase inhibitors (DI) have been identified. These DI induce tumor cells to undergo growth arrest, differentiation, and/or apoptosis in culture and in animal models, at doses that seem to be nontoxic and appear to be selective. Butyrate, a DI that is naturally formed in the human colon, is able to reduce the size and the number of tumors in rat models of bowel cancer.3 In vitro, sodium butyrate (NaB) is a potent differentiating agent for several colorectal cancer cell lines (CRCs).4-6 NaB-mediated cell cycle withdrawal of CRCs appears to be dependent on acetylation of histones and consequent changes in transcription, requiring continuous protein synthesis and the expression of p21. 7 It has recently been shown that 1 mM NaB is the best working concentration to activate the differentiation program in CRCs without triggering apoptosis, whereas 5 mM NaB is sufficient to induce a p53-independent...

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