T-type Ca2+ channel inhibition induces p53-dependent cell growth arrest and apoptosis through activation of p38-MAPK in colon cancer cells.

摘要: Epithelial tumor cells express T-type Ca2+ channels, which are thought to promote cell proliferation. This study investigated the cellular response channel inhibition either by small-molecule antagonists or RNAi-mediated knockdown. Selective caused growth and apoptosis more effectively in HCT116 expressing wild-type p53 (p53wt), than mutant p53−/− cells. These increased p53-dependent gene expression genomic occupancy of at specific target sequences. The knockdown a single subunit (CACNA1G) reduced induced caspase-3/7 activation p53wt as compared with Moreover, CaCo2 that do not functional were made sensitive CACNA1G when was stably expressed. Upon inhibition, p38-MAPK promoted phosphorylation Ser392 p53wt. Cells treated inhibitor SB203580 RNAi targeting p38-MAPKα/β (MAPK14/MAPK11) showed resistance inhibition. Finally, decreased sensitivity associated accumulation genes, p21Cip1 (CDKN1A) BCL2-binding component 3 (BBC3/PUMA). Implications: A novel pathway involving is revealed provides rationale for antitumor therapies channels. Mol Cancer Res; 12(3); 348–58. ©2013 AACR.