Abstract 4425: PARP1 inhibition impedes Warburg effect in breast cancer cells through modulation of the miR-98/STAT3 signaling axis

Abstract

Abstract Cancer cells have increased metabolic autonomy and rewired cellular metabolism in order to meet the bioenergetics, biosynthetic, and redox demands during tumorigenesis. They tend to depend on glycolysis rather than oxidative metabolism to meet their energy demand. Therefore, elucidation of the key regulators of metabolism could potentially aid in devising selective and promising anti-cancer therapies. MicroRNAs (miRNAs) have recently attained prominence as key regulators of cancer cell metabolism. MiRNAs are known to regulate metabolism in cancer cells either through the direct regulation of key metabolic enzymes, tumor suppressors and oncogenes or the indirect modulation of master transcription factors and signalling pathways. Therefore dysregulation of cellular metabolism by miRNAs contributes significantly to cancer progression. Current therapeutic strategies include: (a) targeting metabolic pathways that are strictly required for cancer cells, or (b) impairing an oncogenic signalling axis involved in cancer metabolic rewiring. The poly (ADP-ribose) polymerase (PARP) inhibitors, used in the treatment of DNA repair deficient tumours are also known to facilitate oxidative metabolism. However, the effect of PARP inhibition on glycolytic metabolism is yet to be elucidated. In the present study we aimed to identify novel miRNAs involved in the regulation of glycolytic metabolism after PARP1 inhibition. MiRNA microarray analysis revealed upregulation of the tumor suppressor miR-98 in PARP1 inhibitor treated MDA-MB-231 breast cancer cells. Further mechanistic studies confirmed miR-98 regulation of STAT3 expression and downregulation of key glycolytic enzymes HK2 and PKM2 leading to decreased Warburg effect. MiR-98 overexpression or PARP1 inhibition in combination with miR-98 antagomir showed downregulation of STAT3, HK2 and PKM2. Glucose consumption and HK2 activity were decreased upon PARP1 inhibition associated miR-98 expression. Collectively, these results showed that miR-98 is a critical regulator of PARP1 inhibition associated reduction of Warburg effect in breast cancer cells. Citation Format: Nidhi Shukla. PARP1 inhibition impedes Warburg effect in breast cancer cells through modulation of the miR-98/STAT3 signaling axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4425.