Journal
MOLECULAR CANCER RESEARCH
Volume 12, Issue 3, Pages 348-358Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-13-0485
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Funding
- UVA Department of Radiation Oncology Dr. George Amornio pilot grant [UVA P30 CA44579]
- James and Rebecca Craig fund
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Epithelial tumor cells express T-type Ca2+ channels, which are thought to promote cell proliferation. This study investigated the cellular response to T-type Ca2+ channel inhibition either by small-molecule antagonists or by RNAi-mediated knockdown. Selective T-type Ca2+ 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 Ca2+ 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 Ca2+ channel inhibition, p38-MAPK promoted phosphorylation at Ser392 of p53wt. Cells treated with the inhibitor SB203580 or specific RNAi targeting p38-MAPK alpha/beta (MAPK14/MAPK11) showed resistance to T-type Ca2+ 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). (C)2013 AACR.
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