Abstract
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.
Highlights
Cachexia is a multifactorial syndrome characterized by involuntary weight loss due to skeletal muscle wasting and fat depletion
We examined the effect of silibinin on growth of pancreatic cancer cell lines
Our results demonstrate that silibinin inhibits growth of pancreatic cancer cells in a dose-dependent manner
Summary
Cachexia is a multifactorial syndrome characterized by involuntary weight loss due to skeletal muscle wasting and fat depletion. Often cancer patients are diagnosed with significant body weight loss that limits therapeutic options. Cachectic cancer patients exhibit poorer prognosis in comparison to non-cachectic patients. They have poor survival and response to chemotherapy and radiotherapy as well as significant increase in surgical risk [3]. The most prominent characteristic of the cachexia is significant skeletal muscle depletion which mainly occurs due to enhanced proteolysis and reduced www.impactjournals.com/oncotarget protein synthesis in myofibers [5]. Due to the complex nature and limited understanding of the disease, to date there is no established therapeutic regimen for cancer-induced cachexia
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