Abstract 5483: SIRT1 stabilization provides a therapeutic opportunity for reversing cachexia in pancreatic cancer

Abstract

Abstract Cancer-associated cachexia is a complex metabolic syndrome which leads to excessive loss of skeletal muscle and adipose deposits. Up to 80% of pancreatic cancer patients suffer from cachexia and nearly one third die due to complexities related to the syndrome. Treatment of cachexia will not only improve the standard of living of pancreatic cancer patients but would also improve the patient survival. In the clinic, majority of the cancer patients are diagnosed at the refractory phase of cachexia, which cannot be reversed by dietary interventions. Till late therapies have not shown promising results in clinical trials. Hence, there is an urgent need to identify new targets to combat cancer cachexia. Sirtuins are protein deacetylases which affect the activity of various transcription factors and signaling components. The expression of all the sirtuins were analyzed after culturing mouse myotubes with tumor cell-conditioned media. The expression of SIRT1 decreased consistently upon treatment of myotubes with conditioned media from multiple human pancreatic cancer cell lines. Resveratrol, which is an activator of SIRT1 rescued the wasting phenotype in the myotubes. However, treatment of pancreatic cancer cells with resveratrol also decreased cell proliferation. Hence, we designed in vivo experiments to examine the effect of resveratrol on muscle wasting irrespective of its effects on tumor burden. We generated SIRT1 knockdown pancreatic cancer cell lines and orthotopically implanted them into the pancreas in athymic nude mice. The tumor-bearing mice were subjected to an oral delivery of resveratrol. These studies demonstrated that while resveratrol had limited effect on cancer cells due to SIRT1 knockdown, resveratrol treatment still protected the mice from muscle wasting by stabilizing SIRT1 in muscles. Hence, our results indicate that resveratrol-mediated stabilization of SIRT1 in muscles can revert wasting irrespective of its effects on tumor cells. Overall, our studies demonstrate the therapeutic potential of SIRT1 stabilization by resveratrol or related class of drugs in managing cancer-associated cachexia. Citation Format: Aneesha Dasgupta, Enza Vernucci, Surendra K. Shukla, Scott E. Mulder, Ryan J. King, Jaime Abrego, Nina V. Chaika, Kyla Buettner, Pankaj K. Singh, Pankaj K. Singh. SIRT1 stabilization provides a therapeutic opportunity for reversing cachexia in pancreatic cancer [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 5483.