Channelpedia

PubMed 24362252


Referenced in Channelpedia wiki pages of: none

Automatically associated channels: Cav3.1



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

Authors: Barbara Dziegielewska, David L Brautigan, James M Larner, Jaroslaw Dziegielewski

Journal, date & volume: Mol. Cancer Res., 2014 Mar , 12, 348-58

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24362252


Abstract
Epithelial tumor cells express T-type Ca(2+) channels, which are thought to promote cell proliferation. This study investigated the cellular response to T-type Ca(2+) channel inhibition either by small-molecule antagonists or by RNAi-mediated knockdown. Selective T-type Ca(2+) channel antagonists caused growth inhibition and apoptosis more effectively in HCT116 cells expressing wild-type p53 (p53wt), than in HCT116 mutant p53(-/-) cells. These antagonists increased p53-dependent gene expression and increased genomic occupancy of p53 at specific target sequences. The knockdown of a single T-type Ca(2+) channel subunit (CACNA1G) reduced cell growth and induced caspase-3/7 activation in HCT116 p53wt cells as compared with HCT116 mutant p53(-/-) cells. Moreover, CaCo2 cells that do not express functional p53 were made more sensitive to CACNA1G knockdown when p53wt was stably expressed. Upon T-type Ca(2+) channel inhibition, p38-MAPK promoted phosphorylation at Ser392 of p53wt. Cells treated with the inhibitor SB203580 or specific RNAi targeting p38-MAPKα/β (MAPK14/MAPK11) showed resistance to T-type Ca(2+) channel inhibition. Finally, the decreased sensitivity to channel inhibition was associated with decreased accumulation of p53 and decreased expression of p53 target genes, p21Cip1 (CDKN1A) and BCL2-binding component 3 (BBC3/PUMA).A novel pathway involving p53 and p38-MAPK is revealed and provides a rationale for antitumor therapies that target T-type Ca(2+) channels.