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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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Project description:Temozolomide (TMZ) is an important first-line treatment for glioblastoma (GBM), but there are limitations to TMZ response in terms of durability and dependence on the promoter methylation status of the DNA repair gene O6-methylguanine DNA methyltransferase (MGMT). MGMT-promoter-hypermethylated (MGMT-M) GBMs are more sensitive to TMZ than MGMT-promoter-hypomethylated (MGMT-UM) GBMs. Moreover, TMZ resistance is inevitable even in TMZ-sensitive MGMT-M GBMs. Hence, epigenetic reprogramming strategies are desperately needed in order to enhance TMZ response in both MGMT-M and MGMT-UM GBMs. In this study, we present novel evidence that the epigenetic reactivation of Tumor Suppressor Candidate 3 (TUSC3) can reprogram sensitivity of GBM stem cells (GSCs) to TMZ irrespective of MGMT promoter methylation status. Interrogation of TCGA patient GBM datasets confirmed TUSC3 promoter regulation of TUSC3 expression and also revealed a strong positive correlation between TUSC3 expression and GBM patient survival. Using a combination of loss-of-function, gain-of-function and rescue studies, we demonstrate that TUSC3 reactivation is associated with enhanced TMZ response in both MGMT-M and MGMT-UM GSCs. Further, we provide novel evidence that the demethylating agent 5-Azacitidine (5-Aza) reactivates TUSC3 expression in MGMT-M GSCs, whereas the combination of 5-Aza and MGMT inhibitor Lomeguatrib is necessary for TUSC3 reactivation in MGMT-UM GSCs. Lastly, we propose a pharmacological epigenetic reactivation strategy involving TUSC3 that leads to significantly prolonged survival in MGMT-M and MGMT-UM orthotopic GSCs models. Collectively, our findings provide a framework and rationale to further explore TUSC3-mediated epigenetic reprogramming strategies that could enhance TMZ sensitivity and outcomes in GBM. Mechanistic and translational evidence gained from such studies could contribute towards optimal design of impactful trials for MGMT-UM GBMs that currently do not have good treatment options.

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Gene expression in GBM with Cav3.2 inhibition

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