title: T-type Ca2+ channel inhibition induces p53-dependent cell growth arrest and apoptosis through activation of p38-MAPK in colon cancer cells.
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).
  
  
  CONCLUSIONS
  A novel pathway involving p53 and p38-MAPK is revealed and provides a rationale for antitumor therapies that target T-type Ca(2+) channels.
authors.affiliation: Department of Radiation Oncology, University of Virginia School of Medicine, P.O. Box 800383, Charlottesville, VA 22908. jd5kf@virginia.edu.
authors.forename: Barbara
authors.initials: B
authors.lastname: Dziegielewska
authors.forename: David L
authors.initials: DL
authors.lastname: Brautigan
authors.forename: James M
authors.initials: JM
authors.lastname: Larner
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Dziegielewski
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D018938:Caco-2 Cells; D020747:Calcium Channels, T-Type / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D058990:Molecular Targeted Therapy; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C121855:CACNA1G protein, human; D020747:Calcium Channels, T-Type; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases