title: Inhibition of T-type calcium channels disrupts Akt signaling and promotes apoptosis in glioblastoma cells.
abstract: Glioblastoma multiforme (GBM) are brain tumors that are exceptionally resistant to both radio- and chemotherapy regimens and novel approaches to treatment are needed. T-type calcium channels are one type of low voltage-gated channel (LVCC) involved in embryonic cell proliferation and differentiation; however they are often over-expressed in tumors, including GBM. In this study, we found that inhibition of T-type Ca(2+) channels in GBM cells significantly reduced their survival and resistance to therapy. Moreover, either T-type selective antagonists, such as mibefradil, or siRNA-mediated knockdown of the T-type channel alpha subunits not only reduced cell viability and clonogenic potential, but also induced apoptosis. In response to channel blockade or ablation, we observed reduced phosphorylation of Akt and Rictor, suggesting inhibition of the mTORC2/Akt pathway. This was followed by reduction in phosphorylation of anti-apoptotic Bad and caspases activation. The apoptotic response was specific for T-type Ca(2+) channels, as inhibition of L-type Ca(2+) channels did not induce similar effects. Our results implicate T-type Ca(2+) channels as distinct entities for survival signaling in GBM cells and suggest that they are a novel molecular target for tumor therapy.
authors.affiliation: Department of Radiation Oncology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Nicholas C K
authors.initials: NC
authors.lastname: Valerie
authors.forename: Barbara
authors.initials: B
authors.lastname: Dziegielewska
authors.forename: Amol S
authors.initials: AS
authors.lastname: Hosing
authors.forename: Ewa
authors.initials: E
authors.lastname: Augustin
authors.forename: Lloyd S
authors.initials: LS
authors.lastname: Gray
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: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D020748:Mibefradil / Q000494:pharmacology; D046912:Multiprotein Complexes / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494819:BAD protein, human; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D011838:Radiation-Sensitizing Agents; D051025:bcl-Associated Death Protein; D020748:Mibefradil; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases