Abstract 5226: Non-canonical functions of TERT in glioblastoma pathobiology

Abstract

Mutations in the promotor region of TERT are the most common non-coding mutations across cancers, especially in glioblastoma (GBM), which has a TERT mutation frequency rate over 80%. In the absence of any effective molecular targeting therapy for GBM, elucidating oncogenic signaling of TERT could open new avenues in GBM treatment. Canonically, mutations of TERT, which result in TERT upregulation, maintain telomere length in the nucleus and promote indefinite proliferation of cancer cells. However, a non-canonical function of TERT in the mitochondria has recently been suggested. We screened GBM cell models against a novel small molecule inhibitor (RG1534, Reglagene Inc.) that interferes with the functionality of a mutated hTERT promoter. RG1534 selectively suppresses glioma cell viability without affecting non-transformed normal human astrocytes. More interestingly, RG1534 treatment leads to rapid apoptosis induction in glioma cell lines that does not correlate with the time course of the telomere shortening effect. We further validated this rapid apoptosis behavior in glioma cell lines using siRNA and CRISPR/Cas-9 mediated hTERT knockdown. We also measured the protein expression of TERT in subcellular fractions of glioma cell lines and demonstrated the presence of higher TERT expression in mitochondrial extract compared to the nuclear extract. Finally, using MitoSOX dye we demonstrated significant increase of ROS generation in glioma cells treated with RG1534 as compared to control. In summary, our results demonstrate that non-canonical functions of TERT may play critical role in glioma pathobiology and require more detail investigation. Citation Format: Shayesteh R. Ferdosi, Saumya Bollam, Sen Peng, Brett Taylor, Vijay Gokhale, Laurence Hurley, Michael Berens, Harshil Dhruv. Non-canonical functions of TERT in glioblastoma pathobiology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5226.