Inhibition of T-type calcium channels disrupts Akt signaling and promotes apoptosis in glioblastoma cells

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• 作者：Nicholas C.K. Valerie^a ; Barbara Dziegielewska^a ; Amol S. Hosing^a ; Ewa Augustin^b ; Lloyd S. Gray^c ; David L. Brautigan^d ; ^e ; James M. Larner^a ; ^e ; Jaroslaw Dziegielewski^a ; ^e ; ^{jd5kf@virginia.edu} ; ^{jdzieg@gmail.com}
• 关键词：CACNA1C ; L-type channel subunit Cav1.2 ; CACNA1G ; T-type channel subunit Cav3.1 ; CACNA1H ; T-type channel subunit Cav3.2 ; GBM ; glioblastoma multiforme ; LVCC ; low voltage gated calcium channel
• 刊名：Biochemical Pharmacology
• 出版年：2013
• 出版时间：1 April, 2013
• 年：2013
• 卷：85
• 期：7
• 页码：888-897
• 全文大小：1364 K

文摘

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 Ca²⁺ 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 Ca²⁺ channels, as inhibition of L-type Ca²⁺ channels did not induce similar effects. Our results implicate T-type Ca²⁺ channels as distinct entities for survival signaling in GBM cells and suggest that they are a novel molecular target for tumor therapy.