T-Type Ca_v3.1 Channels Mediate Progression and Chemotherapeutic Resistance in Glioblastoma

T-type Ca²⁺ channels (TTCC) have been identified as key regulators of cancer cell cycle and survival. In vivo studies in glioblastoma (GBM) murine xenografts have shown that drugs able to block TTCC in vitro (such as tetralol derivatives mibefradil/NNC-55-096, or different 3,4-dihydroquinazolines) slow tumor progression. However, currently available TTCC pharmacologic blockers have limited selectivity for TTCC and are unable to distinguish between TTCC isoforms. Here we analyzed the expression of TTCC transcripts in human GBM cells and show a prevalence of Cacna1g/Ca_v3.1 mRNAs. Infection of GBM cells with lentiviral particles carrying short hairpin RNA against Ca_v3.1 resulted in GBM cell death by apoptosis. We generated a murine GBM xenograft via subcutaneous injection of U87-MG GBM cells and found that tumor size was reduced when Ca_v3.1 expression was silenced. Furthermore, we developed an in vitro model of temozolomide-resistant GBM that showed increased expression of Ca_v3.1 accompanied by the activation of macroautophagy. We confirmed a positive correlation between Ca_v3.1 and autophagic markers in both GBM cultures and biopsies. Of note, Ca_v3.1 knockdown resulted in transcriptional downregulation of p62/SQSTM1 and deficient autophagy. Together, these data identify Ca_v3.1 channels as potential targets for slowing GBM progression and recurrence based on their role in regulating autophagy. SIGNIFICANCE: These findings identify Ca_v3.1 calcium channels as a molecular target to regulate autophagy and prevent progression and chemotherapeutic resistance in glioblastoma.