Abstract
Abstract Cancer cachexia is a systemic syndrome characterized by progressive weight loss of the patient due to muscle wasting and fat depletion with or without anorexia. About 80% of pancreatic ductal adenocarcinoma (PDAC) patients exhibits cachectic phenotype and it significantly contributes in mortality and morbidity of the disease. In present study we have evaluated the effect of bioactive molecule silibinin on pancreatic cancer progression and cachectic properties by utilizing in vitro as well as in vivo models of PDAC. We observed that silibinin inhibits growth and induces apoptosis in multiple pancreatic cancer cell lines in a dose-dependent manner. We also observed silibinin-mediated reduction in the expression of key glycolytic genes and inhibition of glucose uptake and lactate secretion. By performing LC-MS/MS based metabolomics, we observed that silibinin treatment leads to global metabolic alterations in pancreatic cancer cells. Pancreatic cancer cells treated with silibinin exhibited reduced expression of c-MYC level, a key metabolic regulator. Furthermore, we observed that silibinin-mediated STAT3 inhibition leads to reduced c-MYC expression. Ectopic expression of constitutively active STAT3 significantly attenuated the effect of silibinin on c-MYC expression and metabolic phenotype of pancreatic cancer cells. Silibinin treatment also inhibited tumor growth and progression of cachexia. Silibinin treatment to tumor-bearing mice also lead to increased food intake, increased grip strength and body coordination. Overall, our results demonstrate that silibinin exhibits anti-cachectic and anti-cancerous properties by inducing metabolic reprogramming in pancreatic cancer cells. Citation Format: Surendra K. Shukla, Aneesha Dasgupta, Kamiya Mehla, Venugopal Gunda, Enza Vernucci, Joshua Soucheck, Gennifer Goode, Ryan King, Anusha Mishra, Ibha Rai, Sangeetha Natrajan, Nina Chaika, Fang Yu, Pankaj K. Singh. Silibinin exhibits anti-cachectic and anti-cancerous property by modulating metabolic properties of pancreatic cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 10.
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