Genomics

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Gene expression in GBM with Cav3.2 inhibition


ABSTRACT: Glioblastoma stem cells (GSCs) have been implicated in tumor initiation, progression and resistance to therapy. We investigated the expression, function, mechanisms of action and therapeutic targeting of T-type calcium channels (Cav3.2) with the FDA approved and repurposed drug mibefradil in glioblastoma (GBM), and GSCs. We found that Cav3.2 is highly expressed in human GBM specimens and enriched in GCSs. Analyses of TCGA and REMBRANDT databases confirmed the upregulation of Cav3.2 in a subset of tumors (TCGA) and showed that overexpression is associated with worse prognosis. Mibefradil and Cav3.2 knockdown inhibited the growth, survival and stemness of GSCs and sensitized them to temozolomide (TMZ) chemotherapy. To investigate the mechanisms of action of Cav3.2 in GSC, we performed proteomic and transcriptomic screenings followed by functional rescue experiments. Inhibition of Cav3.2 altered cancer signaling pathways and gene transcription. Among other, inhibition of Cav3.2 suppressed GSC growth through inhibition of pro-survival pathways AKT/mTOR, and induction of apoptosis through upregulation of survivin, BAX and cleavage of caspase 9 and PARP. Inhibition of Cav3.2 induced a decrease in the expression of oncogenes including PDGFA, PDGFB and TGFB1 and an increase in the expression of tumor suppressors including TNFRSF14 and HSD17B14. In vivo oral administration of Cav3.2 blocker mibefradil significantly inhibited GSC-derived xenograft growth, prolonged animal survival and sensitized the tumors to TMZ. Our study represents the first comprehensive characterization of Cav3.2 in GBM tumors and GSC. The findings establish Cav3.2 inhibition with the repurposed FDA-approved drug mibefradil as a new strategy for GBM therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE95106 | GEO | 2017/08/31

SECONDARY ACCESSION(S): PRJNA376103

REPOSITORIES: GEO

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