Abstract 4837: Inhibition of mitochondrial fission activates glycogen storage to support cell survival in colon cancer

Abstract

Abstract Metabolic reprogramming has been increasingly recognized as one of the major mechanisms that fuels tumorigenesis and disease progression. Our previous studies have shown that in response to fatty acid uptake, colon cancer cells activate mitochondrial fission to support fatty acid oxidation and downstream Wnt signaling. Given the potential benefit of inhibiting mitochondrial fission, Dynamin-Related Protein 1 (Drp1), a pro-fission factor, has become an attractive target for developing anticancer agents. Here we investigated the role of Drp1 in promoting metabolic adaptation in colon cancer. We found that knockdown of Drp1 decreased mitochondrial respiration which resulted in increased glucose uptake and lactate production. In addition, downregulation of Drp1 increased AMP-activated protein kinase (AMPK) activity which coincided with glycogen accumulation. Consistently, results from GC/MS analysis of cellular metabolites revealed that the levels of glucose-6-phosphate, a precursor for glycogenesis, were significantly elevated in Drp1 knockdown cells whereas pyruvate and other TCA cycle metabolites remained unchanged. Mechanistically, AMPK transcriptionally activates the expression of glycogen synthase 1 (GYS1) and hexokinase 2 (HK2) genes and silencing GYS1 abolished the glycogen accumulation phenotype in Drp1 knockdown cells. Using APC-derived 3D organoids, we demonstrated that the glycogen levels were elevated in Apcf/f Drp1f/f tumor organoids upon deletion of Drp1. Similarly, increased GYS1 expression and glycogen levels were detected in xenograft tumors derived from Drp1 knockdown colon cancer cells compared to control. Functionally, increased glycogen storage allowed Drp1 knockdown cells to survive glucose starvation conditions suggesting an enhanced survival capacity compared to control cells. Taken together, our findings indicate that Drp1 inhibition by itself is unlikely to be sufficient to eradicate cancer cells as adaptive metabolic mechanisms are activated to promote cell survival. However, combining Drp1 inhibition may enhance the efficacy of chemotherapeutic agents for colon cancer treatment. Citation Format: Sumati Hasani, Lyndsay E. Young, Moumita Banerjee, Dylan Rivas, Jinhwan Kim, Ramon Sun, Matthew Gentry, Xiaopeng Xiong, Tianyan Gao. Inhibition of mitochondrial fission activates glycogen storage to support cell survival in colon cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4837.