Abstract A08: Telomerase inhibition brings metabolic compromises in glioblastoma multiforme (GBM)

Abstract

Abstract Introduction: A defining characteristic of cancer cells is their ability to circumvent multiple regulatory mechanisms that normally restrict cell proliferation. Understanding the links between aberrant metabolic adaptation and prosurvival responses in glioma cells is crucial towards the development of new anti-glioma therapies. Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of the telomerase holoenzyme. The telomere maintenance or telomerase activity is mainly driven by hTERT and hTERC. A large number of reports suggest an ever increasing role of telomere maintenance in cancer progression. We sought to evaluate its involvement in the regulation of metabolic status in these cells. Methods: Human glioma cell lines A172 and U87MG Cells were grown in DMEM supplemented with 10% FBS. On attaining semi confluence, cells were switched to SFM (serum free media) for 4 hrs and further treated with Telomerase inhibitor for 24hrs. Glioma cell lines were transiently transfected with lipofectamine 2000 and lipofectamine RNAi max reagents. Cells were harvested 48hrs post transfection. Heterotropic glioma xenografts were generated upon injecting U87MG cells subcutaneously in flank region of nude mice. After 20 days of injection, prominent tumor volume was visible. Thereafter, mice were grouped and administered either with PBS or Telomerase inhibitor for 20 days on every alternate day. Mice were sacrificed and tissues were processed for subsequent experiments. Histochemically identified TERT mutant and wild type human glioma samples were also used to unravel the ongoing signaling cascades. Results: Inhibition of telomerase resulted in metabolic compromises. TERT was found to regulate the expression of an important transcription factor responsibe for maintenance of metabolic and antioxidant proteins. The expression of this transcription factor was concomitant with altered metabolic profile as characterized by decreased pentose phosphate pathway. TERT regulated expression of PPP genes seemed to have its effect on prosurvival and antioxidant molecules. Conclusions: hTERT plays a key role in survival responses by modulating the metabolic status of glioma cells both in vitro and in vivo. By switching the signals under the control of a metabolic sensor (transcription factor) that modifies energy status to govern anti proliferative environment, hTERT regulates both survival responses and energy status. Citation Format: Fahim Ahmad, Ellora Sen. Telomerase inhibition brings metabolic compromises in glioblastoma multiforme (GBM). [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A08.