Oncotarget

Research Papers:

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 and Pankaj K. Singh

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Oncotarget. 2015; 6:19118-19131. https://doi.org/10.18632/oncotarget.4078

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Abstract

Surendra K. Shukla1, Venugopal Gunda1, Jaime Abrego1, Dhanya Haridas2, Anusha Mishra1, Joshua Souchek1, Nina V. Chaika1, Fang Yu3, Aaron R. Sasson4, Audrey J. Lazenby5, Surinder K. Batra2, Pankaj K. Singh1,2,5,6

1The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA

2Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA

3Department of Biostatistics, University of Nebraska Medical Center, Omaha, Nebraska, USA

4Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, USA

5Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA

6Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, USA

Correspondence to:

Pankaj K. Singh, e-mail: pankaj.singh@unmc.edu

Keywords: MUC16, metabolism, pancreatic cancer, c-MYC, metabolomics

Received: March 04, 2015     Accepted: May 21, 2015     Published: June 03, 2015

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.


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