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Cancer Res. 2017 Jul 1;77(13):3479-3490. doi: 10.1158/0008-5472.CAN-16-2347. Epub 2017 May 16.

Targetable T-type Calcium Channels Drive Glioblastoma.

Author information

1
Department of Microbiology, Immunology & Cancer Biology, University of Virginia, Charlottesville, Virginia.
2
George Mason University Center for Applied Proteomics and Molecular Medicine, Manassas, Virginia.
3
Department of Public Health Sciences and Bioinformatics Core, Charlottesville, Virginia.
4
Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
5
Case Western Reserve University Neurological Surgery, Cleveland, Ohio.
6
Department of Neurology, University of Virginia, Charlottesville, Virginia.
7
Cavion LLC, Charlottesville, Virginia.
8
Department of Microbiology, Immunology & Cancer Biology, University of Virginia, Charlottesville, Virginia. ra6u@virginia.edu.
9
Cancer Center, University of Virginia, Charlottesville, Virginia.

Abstract

Glioblastoma (GBM) stem-like cells (GSC) promote tumor initiation, progression, and therapeutic resistance. Here, we show how GSCs can be targeted by the FDA-approved drug mibefradil, which inhibits the T-type calcium channel Cav3.2. This calcium channel was highly expressed in human GBM specimens and enriched in GSCs. Analyses of the The Cancer Genome Atlas and REMBRANDT databases confirmed upregulation of Cav3.2 in a subset of tumors and showed that overexpression associated with worse prognosis. Mibefradil treatment or RNAi-mediated attenuation of Cav3.2 was sufficient to inhibit the growth, survival, and stemness of GSCs and also sensitized them to temozolomide chemotherapy. Proteomic and transcriptomic analyses revealed that Cav3.2 inhibition altered cancer signaling pathways and gene transcription. Cav3.2 inhibition suppressed GSC growth in part by inhibiting prosurvival AKT/mTOR pathways and stimulating proapoptotic survivin and BAX pathways. Furthermore, Cav3.2 inhibition decreased expression of oncogenes (PDGFA, PDGFB, and TGFB1) and increased expression of tumor suppressor genes (TNFRSF14 and HSD17B14). Oral administration of mibefradil inhibited growth of GSC-derived GBM murine xenografts, prolonged host survival, and sensitized tumors to temozolomide treatment. Our results offer a comprehensive characterization of Cav3.2 in GBM tumors and GSCs and provide a preclinical proof of concept for repurposing mibefradil as a mechanism-based treatment strategy for GBM. Cancer Res; 77(13); 3479-90. ©2017 AACR.

PMID:
28512247
PMCID:
PMC5505315
DOI:
10.1158/0008-5472.CAN-16-2347
[Indexed for MEDLINE]
Free PMC Article

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