Abstract 5407: T-type Ca2+ channel inhibitors sensitize ovarian cancer to carboplatin through downregulation of survivin gene expression

Abstract

Abstract Recent studies by our group and others have shown that T-type Ca2+ channels play a reinforcing role in cancer cell proliferation, cell cycle progression and apoptosis evasion. We have demonstrated drug cooperativity between T-type Ca2+ channel inhibitor, mibefradil and carboplatin in vivo in ovarian cancer xenografts. To investigate the molecular mechanism by which T-type Ca2+ channels affect tumor growth, we used a panel of ovarian cancer cell lines together with mibefradil or small interfering RNA (siRNA) to silence the T-channels gene expression. Inhibition of T-type Ca2+ channels with mibefradil or by silencing expression resulted in growth suppression in ovarian cancer with simultaneous increase in apoptosis and decrease in expression of the anti-apoptotic gene survivin (BIRC5). Combining carboplatin with mibefradil resulted in increased apoptosis. Analysis of intracellular signaling revealed T-type Ca2+ channel inhibitors induced changes in the levels of FOXO proteins, which regulate BIRC5 gene expression. Mibefradil treatment caused greater nuclear retention of FoxO1 and FoxO3a, two transcription factors that repress BIRC5 expression, while protein expression of the transcription factor that activates BIRC5 expression, FoxM1, decreased. Chromatin immunoprecipitation of FOXO proteins from mibefradil treated ovarian cancer cells demonstrated binding of FoxM1 and FoxO1 within the BIRC5 (survivin) promoter. Together, the data show that T-type Ca2+ channels support ovarian cancer cell cycle, proliferation and regulate pro-survival pathways through the FOXO-survivin signaling axis, which has been reported to be deregulated in ovarian cancer. Moreover, our results provide the rationale for future use of T-type antagonists as sensitizing agents in combination with standard chemotherapeutics. Citation Format: Barbara Dziegielewska, Eli V. Casarez, Wesley Z. Yang, Jaroslaw Dziegielewski, Jill K. Slack-Davis. T-type Ca2+ channel inhibitors sensitize ovarian cancer to carboplatin through downregulation of survivin gene expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5407. doi:10.1158/1538-7445.AM2015-5407