title: MUC16-mediated activation of mTOR and c-Myc reprograms pancreatic cancer metabolism.
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.
authors.affiliation: The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Surendra K
authors.initials: SK
authors.lastname: Shukla
authors.affiliation: The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Venugopal
authors.initials: V
authors.lastname: Gunda
authors.affiliation: The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Abrego
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Dhanya
authors.initials: D
authors.lastname: Haridas
authors.affiliation: The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Anusha
authors.initials: A
authors.lastname: Mishra
authors.affiliation: The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Souchek
authors.affiliation: The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Nina V
authors.initials: NV
authors.lastname: Chaika
authors.affiliation: Department of Biostatistics, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Yu
authors.affiliation: Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Sasson
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Audrey J
authors.initials: AJ
authors.lastname: Lazenby
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Batra
authors.affiliation: The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA.|Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA.|Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA.|Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Pankaj K
authors.initials: PK
authors.lastname: Singh
mesh_terms: D018394:CA-125 Antigen / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D018394:CA-125 Antigen; C451759:MUC16 protein, human; C489427:MYC protein, human; D008565:Membrane Proteins; D016271:Proto-Oncogene Proteins c-myc; D019344:Lactic Acid; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D005947:Glucose
keywords: MUC16; c-MYC; metabolism; metabolomics; pancreatic cancer