TY - JOUR
T1 - A novel cell type-specific role of p38α in the control of autophagy and cell death in colorectal cancer cells
AU - Comes, F.
AU - Matrone, A.
AU - Lastella, P.
AU - Nico, B.
AU - Susca, F. C.
AU - Bagnulo, R.
AU - Ingravallo, G.
AU - Modica, S.
AU - Lo Sasso, G.
AU - Moschetta, A.
AU - Guanti, G.
AU - Simone, C.
N1 - Funding Information:
Acknowledgements. We thank Marie Basso for her editorial assistance; Drs FP Jori, N Resta and A Stella, for their helpful discussion during the preparation of the manuscript. This work was partly supported by a grant from the Associazione Italiana Ricerca sul Cancro (to AM) and a grant from Fondazione CARIME (to GG).
PY - 2007/4
Y1 - 2007/4
N2 - 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 p38α/β kinases. We report that p38α 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 p38α 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 p38α as a central mediator of colorectal cancer cell homeostasis and establish a rationale for the evaluation of the pharmacological manipulation of the p38α pathway in the treatment of colorectal cancer.
AB - 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 p38α/β kinases. We report that p38α 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 p38α 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 p38α as a central mediator of colorectal cancer cell homeostasis and establish a rationale for the evaluation of the pharmacological manipulation of the p38α pathway in the treatment of colorectal cancer.
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U2 - 10.1038/sj.cdd.4402076
DO - 10.1038/sj.cdd.4402076
M3 - Article
C2 - 17159917
AN - SCOPUS:33947418965
SN - 1350-9047
VL - 14
SP - 693
EP - 702
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 4
ER -