title: Glutamine promotes ovarian cancer cell proliferation through the mTOR/S6 pathway.
abstract: Glutamine is one of the main nutrients used by tumor cells for biosynthesis. Therefore, targeted inhibition of glutamine metabolism may have anti-tumorigenic implications. In the present study, we aimed to evaluate the effects of glutamine on ovarian cancer cell growth. Three ovarian cancer cell lines, HEY, SKOV3, and IGROV-1, were assayed for glutamine dependence by analyzing cytotoxicity, cell cycle progression, apoptosis, cell stress, and glucose/glutamine metabolism. Our results revealed that administration of glutamine increased cell proliferation in all three ovarian cancer cell lines in a dose dependent manner. Depletion of glutamine induced reactive oxygen species and expression of endoplasmic reticulum stress proteins. In addition, glutamine increased the activity of glutaminase (GLS) and glutamate dehydrogenase (GDH) by modulating the mTOR/S6 and MAPK pathways. Inhibition of mTOR activity by rapamycin or blocking S6 expression by siRNA inhibited GDH and GLS activity, leading to a decrease in glutamine-induced cell proliferation. These studies suggest that targeting glutamine metabolism may be a promising therapeutic strategy in the treatment of ovarian cancer.
authors.affiliation: Department of Gynecologic OncologyShanDong Tumor Hospital and Cancer Institute, Jinan University, Jinan 250117, People's Republic of ChinaDivision of Gynecologic OncologyUniversity of North Carolina at Chapel Hill, CB #7572, Physicians Office Building Rm #B105, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Department of Gynecologic OncologyShanDong Tumor Hospital and Cancer Institute, Jinan University, Jinan 250117, People's Republic of ChinaDivision of Gynecologic OncologyUniversity of North Carolina at Chapel Hill, CB #7572, Physicians Office Building Rm #B105, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Lingqin
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Department of Gynecologic OncologyShanDong Tumor Hospital and Cancer Institute, Jinan University, Jinan 250117, People's Republic of ChinaDivision of Gynecologic OncologyUniversity of North Carolina at Chapel Hill, CB #7572, Physicians Office Building Rm #B105, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Xiugui
authors.initials: X
authors.lastname: Sheng
authors.affiliation: Department of Gynecologic OncologyShanDong Tumor Hospital and Cancer Institute, Jinan University, Jinan 250117, People's Republic of ChinaDivision of Gynecologic OncologyUniversity of North Carolina at Chapel Hill, CB #7572, Physicians Office Building Rm #B105, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Adam K
authors.initials: AK
authors.lastname: Willson
authors.affiliation: Department of Gynecologic OncologyShanDong Tumor Hospital and Cancer Institute, Jinan University, Jinan 250117, People's Republic of ChinaDivision of Gynecologic OncologyUniversity of North Carolina at Chapel Hill, CB #7572, Physicians Office Building Rm #B105, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Dario R
authors.initials: DR
authors.lastname: Roque
authors.affiliation: Department of Gynecologic OncologyShanDong Tumor Hospital and Cancer Institute, Jinan University, Jinan 250117, People's Republic of ChinaDivision of Gynecologic OncologyUniversity of North Carolina at Chapel Hill, CB #7572, Physicians Office Building Rm #B105, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Stine
authors.affiliation: Department of Gynecologic OncologyShanDong Tumor Hospital and Cancer Institute, Jinan University, Jinan 250117, People's Republic of ChinaDivision of Gynecologic OncologyUniversity of North Carolina at Chapel Hill, CB #7572, Physicians Office Building Rm #B105, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Department of Gynecologic OncologyShanDong Tumor Hospital and Cancer Institute, Jinan University, Jinan 250117, People's Republic of ChinaDivision of Gynecologic OncologyUniversity of North Carolina at Chapel Hill, CB #7572, Physicians Office Building Rm #B105, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Gynecologic OncologyShanDong Tumor Hospital and Cancer Institute, Jinan University, Jinan 250117, People's Republic of ChinaDivision of Gynecologic OncologyUniversity of North Carolina at Chapel Hill, CB #7572, Physicians Office Building Rm #B105, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Jones
authors.affiliation: Department of Gynecologic OncologyShanDong Tumor Hospital and Cancer Institute, Jinan University, Jinan 250117, People's Republic of ChinaDivision of Gynecologic OncologyUniversity of North Carolina at Chapel Hill, CB #7572, Physicians Office Building Rm #B105, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Department of Gynecologic OncologyShanDong Tumor Hospital and Cancer Institute, Jinan University, Jinan 250117, People's Republic of ChinaDivision of Gynecologic OncologyUniversity of North Carolina at Chapel Hill, CB #7572, Physicians Office Building Rm #B105, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA victoria_baejump@med.unc.edu czhou@med.unc.edu.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Gynecologic OncologyShanDong Tumor Hospital and Cancer Institute, Jinan University, Jinan 250117, People's Republic of ChinaDivision of Gynecologic OncologyUniversity of North Carolina at Chapel Hill, CB #7572, Physicians Office Building Rm #B105, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Department of Gynecologic OncologyShanDong Tumor Hospital and Cancer Institute, Jinan University, Jinan 250117, People's Republic of ChinaDivision of Gynecologic OncologyUniversity of North Carolina at Chapel Hill, CB #7572, Physicians Office Building Rm #B105, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA victoria_baejump@med.unc.edu czhou@med.unc.edu.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Bae-Jump
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000494:pharmacology*; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D005973:Glutamine; D019344:Lactic Acid; D000255:Adenosine Triphosphate; C546842:MTOR protein, human; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose
keywords: glutamate dehydrogenase; glutaminase; mTOR/S6; ovarian cancer; siRNA