title: Enhanced mitochondrial glutamine anaplerosis suppresses pancreatic cancer growth through autophagy inhibition.
abstract: Cancer cells use precursors derived from tricarboxylic acid (TCA) cycle to support their unlimited growth. However, continuous export of TCA cycle intermediates results in the defect of mitochondrial integrity. Mitochondria glutamine metabolism plays an essential role for the maintenance of mitochondrial functions and its biosynthetic roles by refilling the mitochondrial carbon pool. Here we report that human pancreatic ductal adenocarcinoma (PDAC) cells have a distinct dependence on mitochondrial glutamine metabolism. Whereas glutamine flux into mitochondria contributes to proliferation of most cancer cells, enhanced glutamine anaplerosis results in a pronounced suppression of PDAC growth. A cell membrane permeable α-ketoglutarate analog or overexpression of glutamate dehydrogenase lead to decreased proliferation and increased apoptotic cell death in PDAC cells but not other cancer cells. We found that enhanced glutamine anaplerosis inhibits autophagy, required for tumorigenic growth of PDAC, by activating mammalian TORC1. Together, our results reveal that glutamine anaplerosis is a crucial regulator of growth and survival of PDAC cells, which may provide novel therapeutic approaches to treat these cancers.
authors.affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.|Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.
authors.forename: Seung Min
authors.initials: SM
authors.lastname: Jeong
authors.affiliation: School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Sunsook
authors.initials: S
authors.lastname: Hwang
authors.affiliation: School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Kyungsoo
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.|Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.
authors.forename: Seungyeon
authors.initials: S
authors.lastname: Yang
authors.affiliation: School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Rho Hyun
authors.initials: RH
authors.lastname: Seong
mesh_terms: D001343:Autophagy; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D009363:Neoplasm Proteins; D018698:Glutamic Acid; D000076222:Mechanistic Target of Rapamycin Complex 1