title: Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer.
abstract: Glutamine can play a critical role in cellular growth in multiple cancers. Glutamine-addicted cancer cells are dependent on glutamine for viability, and their metabolism is reprogrammed for glutamine utilization through the tricarboxylic acid (TCA) cycle. Here, we have uncovered a missing link between cancer invasiveness and glutamine dependence. Using isotope tracer and bioenergetic analysis, we found that low-invasive ovarian cancer (OVCA) cells are glutamine independent, whereas high-invasive OVCA cells are markedly glutamine dependent. Consistent with our findings, OVCA patients' microarray data suggest that glutaminolysis correlates with poor survival. Notably, the ratio of gene expression associated with glutamine anabolism versus catabolism has emerged as a novel biomarker for patient prognosis. Significantly, we found that glutamine regulates the activation of STAT3, a mediator of signaling pathways which regulates cancer hallmarks in invasive OVCA cells. Our findings suggest that a combined approach of targeting high-invasive OVCA cells by blocking glutamine's entry into the TCA cycle, along with targeting low-invasive OVCA cells by inhibiting glutamine synthesis and STAT3 may lead to potential therapeutic approaches for treating OVCAs.
authors.affiliation: Laboratory for Systems Biology of Human Diseases, Rice University, Houston, TX, USA.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Yang
authors.forename: Tyler
authors.initials: T
authors.lastname: Moss
authors.forename: Lingegowda S
authors.initials: LS
authors.lastname: Mangala
authors.forename: Juan
authors.initials: J
authors.lastname: Marini
authors.forename: Hongyun
authors.initials: H
authors.lastname: Zhao
authors.forename: Stephen
authors.initials: S
authors.lastname: Wahlig
authors.forename: Guillermo
authors.initials: G
authors.lastname: Armaiz-Pena
authors.forename: Dahai
authors.initials: D
authors.lastname: Jiang
authors.forename: Abhinav
authors.initials: A
authors.lastname: Achreja
authors.forename: Julia
authors.initials: J
authors.lastname: Win
authors.forename: Rajesha
authors.initials: R
authors.lastname: Roopaimoole
authors.forename: Cristian
authors.initials: C
authors.lastname: Rodriguez-Aguayo
authors.forename: Imelda
authors.initials: I
authors.lastname: Mercado-Uribe
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.forename: Prahlad T
authors.initials: PT
authors.lastname: Ram
authors.forename: Deepak
authors.initials: D
authors.lastname: Nagrath
mesh_terms: D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D015398:Signal Transduction / Q000235:genetics
chemical_list: D005973:Glutamine