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

被引:116
作者
Comes, F.
Matrone, A.
Lastella, P.
Nico, B.
Susca, F. C.
Bagnulo, R.
Ingravallo, G.
Modica, S.
Lo Sasso, G.
Moschetta, A.
Guanti, G. [1 ]
Simone, C.
机构
[1] Univ Bari, Div Med Genet, Dept Biomed Childhood, Bari, Italy
[2] Univ Bari, Dept Human Anat & Histol, Bari, Italy
[3] Univ Bari, Dept Pathol Anat, Bari, Italy
[4] Univ Bari, Consorzio Mario Negri Sud, Santa Maria Imbaro Ch, Bari, Italy
[5] Univ Bari, Clin Med Mum, Dept Internal Med, Bari, Italy
[6] Temple Univ, Sbarro Inst Canc Res & Mol Med, Ctr Biotechnol, Coll Sci & Technol, Philadelphia, PA 19122 USA
关键词
colorectal cancer; p38; alpha; autophagic cell death; apoptosis; SB202190;
D O I
10.1038/sj.cdd.4402076
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 p38 alpha/beta kinases. We report that p38 alpha 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 p38 alpha 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 p38 alpha as a central mediator of colorectal cancer cell homeostasis and establish a rationale for the evaluation of the pharmacological manipulation of the p38 alpha pathway in the treatment of colorectal cancer.
引用
收藏
页码:693 / 702
页数:10
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