Abstract 3376: Targeting metabolic flux of tumor cells to prevent pancreatic cancer associated cachexia

Abstract

Abstract Cancer associated cachexia is a complex metabolic syndrome characterized by excessive loss of skeletal muscle and adipose tissue. Cancer-induced cachexia accounts for nearly 20% of all cancer-related deaths and is most prevalent in patients with gastric, pancreatic, colon and lung cancer. More than 80% pancreatic cancer patients exhibit cachectic phenotype. Although association of cachexia with cancer is known for a long time, the molecular mechanism of cancer-induced cachexia is still not well understood. Better understanding of the cancer-related cachexia syndrome may provide novel therapeutic targets for enhancing the quality of life of cancer patients. Several studies have demonstrated that multiple cytokines and cachectic factors secreted by tumor cells contribute to cancer associated cachexia. Because most of the cancer cells present metabolic alterations, which may contribute to secretion of cachectic cytokines and metabolites involved in cancer-induced cachexia. By culturing differentiated C2C12 and 3T3-L1 cells in the presence of pancreatic adenocarcinoma cell or immortalized epithelial cell supernatants, we established cell culture-based cachexia model systems to investigate the depletion of muscle mass and fatty acid content. To study the role of metabolic pathways in tumor cells on cachectic factor secretion, we pre-treated pancreatic cancer cells with different metabolic inhibitors like 2-Deoxy-D-glucose (2-DG), 3-Bromopyruvic acid (3-BrPA) , bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulphide (BPTES) and collected conditioned medium from pre-treated cancer cells at different time points. Further, we accessed the cachectic potential of these conditioned media along with control conditioned medium. Physiological and biochemical alterations during muscle fiber breakdown and adipocyte fat depletion were assayed by performing real-time PCR and cell imaging. We observed that inhibition of glycolysis with 3-BrPA & 2-DG and inhibition of glutaminolysis with BPTES in tumor cells causes decreased muscle fiber breakdown and adipocytes fat depletion. Our results demonstrates crucial role of tumor cell metabolic alterations in cancer-induced cachexia. Citation Format: Surendra K. Shukla, Pankaj K. Singh. Targeting metabolic flux of tumor cells to prevent pancreatic cancer associated cachexia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3376. doi:10.1158/1538-7445.AM2014-3376