Abstract 273: Synergistically suppressive effects by combination of glycolytic inhibitor with TRAP1-depletion in colorectal cancer

Abstract

Abstract Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial homolog of HSP90 chaperones. It plays an important role in protection against oxidative stress and apoptosis by regulating reactive oxidative species (ROS). Recent studies have suggested TRAP1 as a regulator of metabolism and mitochondrial homeostasis in diverse pathological states, including cancer. To further elucidate the mechanistic role of TRAP1 in regulating tumor cell survival, we used gamitrinib-triphenylphosphonium (G-TPP) to inhibit TRAP1 signaling pathways in colon cancer. Inhibition of TRAP1 disrupted redox homeostasis and increased ER stress in colon cancer. To confirm the G-TPP effects of TRAP1 inhibition in colon cancer, we performed TRAP1 CRISPR/Cas9 to deplete TRAP1 expression in colon cancer cell line CT26. TRAP1-depleted cells were found to acquire several distinct phenotypes: induction of reactive oxidative species (ROS) level, reduction of cell growth, and lower pH value of culture medium. In addition, proteomic data showed that depletion of TRAP1 induced significant metabolism alteration in CT26 cells. Using seahorse assay to access mitochondrial respiration and glycolysis, we found that TRAP1-depleted cells were insensitive to Oxidative Phosphorylation (OXPHOS) inhibitor treatment and significantly increased extracellular acidification rate (ECAR) compared to parental cells. Furthermore, higher glucose consumption rate and higher lactic acid level of culture medium were observed in TRAP1-depleted cells. On the other hand, Glycolytic inhibitor (2DG) led to excessive ROS production, reduction of glucose uptake and exacerbated cell death in TRAP1-depleted cell compared to parental cells. Taken together, depletion of TRAP1 induces mitochondrial dysfunction and modulates metabolic switch toward aerobic glycolysis in TRAP1-depleted colon cancer cells. Dual inhibition of TRAP1 and glycolytic signaling may increase therapeutic efficiency through induction of excessive ROS production in colon cancer. Citation Format: Hong-Yuan Tsai, Miao-Hsueh Chen, Herath Lakmini Senavirathna, Jihye Yun, Sheng Pan, Ru Chen. Synergistically suppressive effects by combination of glycolytic inhibitor with TRAP1-depletion in colorectal 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 273.