Silibinin-mediated metabolic reprogramming attenuates pancreatic cancer-induced cachexia and tumor growth

Surendra K. Shukla, Aneesha Dasgupta, Kamiya Mehla, Venugopal Gunda, Enza Vernucci, Joshua Souchek, Gennifer Goode, Ryan King, Anusha Mishra, Ibha Rai, Sangeetha Nagarajan, Nina V. Chaika, Fang Yu, Pankaj K. Singh

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancerrelated 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 tumorbearing mice. In conclusion, silibinin-induced metabolic reprogramming diminishes cell growth and cachectic properties of pancreatic cancer cells and animal models.

Original languageEnglish (US)
Pages (from-to)41146-41161
Number of pages16
JournalOncotarget
Volume6
Issue number38
DOIs
StatePublished - 2015

Keywords

  • C-Myc
  • Cachexia
  • Cancer metabolism
  • Pancreatic cancer
  • Silibinin

ASJC Scopus subject areas

  • Oncology

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