Abstract 5389: Adaptive OXPHOS and antioxidant defense in glucose-deprivation-resistant colon cancer cells

Abstract Cancer cells are generally characterized by exhibiting the Warburg effect, favoring glycolysis over oxidative phosphorylation (OXPHOS) to produce ATP. This leads to an increase in glucose uptake and lactate production, fueling rapid proliferation by providing energy and intermediates for biosynthesis. In parallel, slow angiogenesis resulting in a blood supply insufficient for the tumor's rapid growth leads to glucose starvation in solid tumors. To mimic glucose starvation in vitro, we used a model of glucose deprivation in HCT116 cells. A Seahorse study demonstrated that HCT116 cells endured an adaptive state of dormancy during glucose deprivation, shifting their metabolic pathway from glycolysis to OXPHOS. Interestingly, a small percentage of survived cells after dormancy completely resumed their proliferative abilities without glucose supply. We showed that these glucose-deprivation-resistant (GDR) cells have significant activation in the tricarboxylic acid (TCA) cycle, as well as increased levels of antioxidants and their precursors, such as GSSG, GSH, glutamine, glutamate, proline, betaine, citrulline, and arginine. These findings suggest that GDR cells could scavenge reactive oxygen species (ROS) generated during accelerated OXPHOS. Furthermore, the GDR cells demonstrated additional resistance to oxidative stress, induced by hydrogen peroxide. Increased OXPHOS in dormant cells, associated with elevated ROS production, led to significant DNA damage. In turn, enhancing DNA repair mechanisms and boosting antioxidant activity in GDR cells were accompanied with one-carbon metabolism, supporting rapid proliferation by supplying nucleotides for DNA repair and synthesis. We believe that cancer cells which, under glucose starvation, can completely switch their metabolism from glycolysis to OXPHOS are able to survive and regain their proliferative capacity by boosting their antioxidant defenses and improving their DNA repair mechanisms. This phenomenon supports the thesis that targeting cancer cells' metabolic flexibility and antioxidant capacity is an effective anticancer therapeutic strategy. Citation Format: Elimelech Nesher, Subha Ranjan Das, Bar Levi, Igor Koman. Adaptive OXPHOS and antioxidant defense in glucose-deprivation-resistant colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5389.