MUC16-mediated activation of mTOR and c-MYC reprograms pancreatic cancer metabolism

Surendra K. Shukla, Venugopal Gunda, Jaime Abrego, Dhanya Haridas, Anusha Mishra, Joshua Souchek, Nina V. Chaika, Fang Yu, Aaron R. Sasson, Audrey J. Lazenby, Surinder K. Batra, Pankaj K. Singh

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

MUC16, a transmembrane mucin, facilitates pancreatic adenocarcinoma progression and metastasis. In the current studies, we observed that MUC16 knockdown pancreatic cancer cells exhibit reduced glucose uptake and lactate secretion along with reduced migration and invasion potential, which can be restored by supplementing the culture media with lactate, an end product of aerobic glycolysis. MUC16 knockdown leads to inhibition of mTOR activity and reduced expression of its downstream target c-MYC, a key player in cellular growth, proliferation and metabolism. Ectopic expression of c-MYC in MUC16 knockdown pancreatic cancer cells restores the altered cellular physiology. Our LC-MS/MS based metabolomics studies indicate global metabolic alterations in MUC16 knockdown pancreatic cancer cells, as compared to the controls. Specifically, glycolytic and nucleotide metabolite pools were significantly decreased. We observed similar metabolic alterations that correlated with MUC16 expression in primary tumor tissue specimens from human pancreatic adenocarcinoma cancer patients. Overall, our results demonstrate that MUC16 plays an important role in metabolic reprogramming of pancreatic cancer cells by increasing glycolysis and enhancing motility and invasiveness.

Original languageEnglish (US)
Pages (from-to)19118-19131
Number of pages14
JournalOncotarget
Volume6
Issue number22
DOIs
StatePublished - Jan 1 2015

Keywords

  • MUC16
  • Metabolism
  • Metabolomics
  • Pancreatic cancer
  • c-MYC

ASJC Scopus subject areas

  • Oncology

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    Shukla, S. K., Gunda, V., Abrego, J., Haridas, D., Mishra, A., Souchek, J., Chaika, N. V., Yu, F., Sasson, A. R., Lazenby, A. J., Batra, S. K., & Singh, P. K. (2015). MUC16-mediated activation of mTOR and c-MYC reprograms pancreatic cancer metabolism. Oncotarget, 6(22), 19118-19131. https://doi.org/10.18632/oncotarget.4078