Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth
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Surendra K. Shukla1, Aneesha Dasgupta1,2, Kamiya Mehla1, Venugopal Gunda1, Enza Vernucci1, Joshua Souchek1, Gennifer Goode1, Ryan King1, Anusha Mishra1, Ibha Rai1, Sangeetha Nagarajan1, Nina V. Chaika1, Fang Yu3, Pankaj K. Singh1,2,4,5
1The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA
2Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA
3Department of Biostatistics, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA
4Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA
5Department of Genetics Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA
Pankaj K. Singh, e-mail: email@example.com
Keywords: pancreatic cancer, cancer metabolism, silibinin, cachexia, c-Myc
Received: August 19, 2015 Accepted: September 25, 2015 Published: October 16, 2015
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US. Cancer-associated cachexia is present in up to 80% of PDAC patients and is associated with aggressive disease and poor prognosis. In the present studies we evaluated an anti-cancer natural product silibinin for its effectiveness in targeting pancreatic cancer aggressiveness and the cachectic properties of pancreatic cancer cells and tumors. Our results demonstrate that silibinin inhibits pancreatic cancer cell growth in a dose-dependent manner and reduces glycolytic activity of cancer cells. Our LC-MS/MS based metabolomics data demonstrates that silibinin treatment induces global metabolic reprogramming in pancreatic cancer cells. Silibinin treatment diminishes c-MYC expression, a key regulator of cancer metabolism. Furthermore, we observed reduced STAT3 signaling in silibinin-treated cancer cells. Overexpression of constitutively active STAT3 was sufficient to substantially revert the silibinin-induced downregulation of c-MYC and the metabolic phenotype. Our in vivo investigations demonstrate that silibinin reduces tumor growth and proliferation in an orthotopic mouse model of pancreatic cancer and prevents the loss of body weight and muscle. It also improves physical activity including grip strength and latency to fall in tumor-bearing mice. In conclusion, silibinin-induced metabolic reprogramming diminishes cell growth and cachectic properties of pancreatic cancer cells and animal models.
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