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.
Highlights
Intracellular Ca2+ regulates many cellular processes, including cell cycle, proliferation, transcription, exocytosis, hormone release, cell motility and apoptosis [1,2]
cyclic-AMP response element binding protein (CREB) transcription factor could be responsible for radiation resistance through regulation of DNA repair genes [20], while intracellular Ca2+ and calmodulin dependent kinase II (CaMKII) could regulate efficient p53 activation upon 5-fluorouracil treatment that involves activated p38-mitogen-activated protein kinase (MAPK) [19]
In this study we evaluated the actions of T-type Ca2+ channels using two isogenic epithelial colon carcinoma cell lines, HCT116 p53 wild type and the HCT116 p53-deleted counterpart (HCT116 p53-/-)
Summary
Intracellular Ca2+ regulates many cellular processes, including cell cycle, proliferation, transcription, exocytosis, hormone release, cell motility and apoptosis [1,2]. Aberrant expression of T-type Ca2+ channels in cancer cells is thought to promote cell survival, proliferation and motility [3,11], the molecular mechanisms for these effects are poorly understood. Increased CaMKII activity regulates gene expression directly through phosphorylation of transcription factors, such as cyclic-AMP response element binding protein (CREB) (reviewed in [17]) or indirectly involving p53 activation [18,19]. CREB transcription factor could be responsible for radiation resistance through regulation of DNA repair genes [20], while intracellular Ca2+ and CaMKII could regulate efficient p53 activation upon 5-fluorouracil treatment that involves activated p38-MAPK [19]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
