PMID- 36269753 OWN - NLM STAT- MEDLINE DCOM- 20221107 LR - 20221107 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 17 IP - 10 DP - 2022 TI - Inhibiting glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells. PG - e0276579 LID - 10.1371/journal.pone.0276579 [doi] LID - e0276579 AB - Metabolic reprogramming is now considered a hallmark of cancer cells. KRas-driven cancer cells use glutaminolysis to generate the tricarboxylic acid cycle intermediate alpha-ketoglutarate via a transamination reaction between glutamate and oxaloacetate. We reported previously that exogenously supplied unsaturated fatty acids could be used to synthesize phosphatidic acid-a lipid second messenger that activates both mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and mTOR complex 2 (mTORC2). A key target of mTORC2 is Akt-a kinase that promotes survival and regulates cell metabolism. We report here that mono-unsaturated oleic acid stimulates the phosphorylation of ATP citrate lyase (ACLY) at the Akt phosphorylation site at S455 in an mTORC2 dependent manner. Inhibition of ACLY in KRas-driven cancer cells in the absence of serum resulted in loss of cell viability. We examined the impact of glutamine (Gln) deprivation in combination with inhibition of ACLY on the viability of KRas-driven cancer cells. While Gln deprivation was somewhat toxic to KRas-driven cancer cells by itself, addition of the ACLY inhibitor SB-204990 increased the loss of cell viability. However, the transaminase inhibitor aminooxyacetate was minimally toxic and the combination of SB-204990 and aminooxtacetate led to significant loss of cell viability and strong cleavage of poly-ADP ribose polymerase-indicating apoptotic cell death. This effect was not observed in MCF7 breast cancer cells that do not have a KRas mutation or in BJ-hTERT human fibroblasts which have no oncogenic mutation. These data reveal a synthetic lethality between inhibition of glutamate oxaloacetate transaminase and ACLY inhibition that is specific for KRas-driven cancer cells and the apparent metabolic reprogramming induced by activating mutations to KRas. FAU - Hatipoglu, Ahmet AU - Hatipoglu A AD - Department of Biological Sciences, Hunter College of the City University of New York, New York, New York, United States of America. AD - Biochemistry Program, Graduate Center of the City University of New York, New York, New York, United States of America. FAU - Menon, Deepak AU - Menon D AD - Department of Biological Sciences, Hunter College of the City University of New York, New York, New York, United States of America. AD - Biochemistry Program, Graduate Center of the City University of New York, New York, New York, United States of America. FAU - Levy, Talia AU - Levy T AD - Department of Biological Sciences, Hunter College of the City University of New York, New York, New York, United States of America. FAU - Frias, Maria A AU - Frias MA AD - Department of Biological Sciences, Hunter College of the City University of New York, New York, New York, United States of America. AD - Department of Biology and Health Promotion, St Francis College, Brooklyn, New York, New York, United States of America. FAU - Foster, David A AU - Foster DA AUID- ORCID: 0000-0003-0900-6946 AD - Department of Biological Sciences, Hunter College of the City University of New York, New York, New York, United States of America. AD - Biochemistry Program, Graduate Center of the City University of New York, New York, New York, United States of America. AD - Biology Program, Graduate Center of the City University of New York, New York, New York, United States of America. AD - Department of Pharmacology, Weill Cornell Medicine, New York, New York, United States of America. LA - eng GR - R01 CA179542/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20221021 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 20762-30-5 (Adenosine Diphosphate Ribose) RN - 14I68GI3OQ (Aminooxyacetic Acid) RN - EC 2.3.3.8 (ATP Citrate (pro-S)-Lyase) RN - 0 (Glutamates) RN - 0RH81L854J (Glutamine) RN - 0 (Ketoglutaric Acids) RN - 0 (KRAS protein, human) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - 0 (Oleic Acids) RN - 0 (Oxaloacetates) RN - 0 (Phosphatidic Acids) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.6.1.- (Transaminases) SB - IM MH - Humans MH - Adenosine Diphosphate Ribose MH - Aminooxyacetic Acid MH - *ATP Citrate (pro-S)-Lyase/genetics/metabolism MH - Glutamates/genetics MH - *Glutamine/antagonists & inhibitors/metabolism MH - Ketoglutaric Acids MH - Mechanistic Target of Rapamycin Complex 1/genetics MH - Mechanistic Target of Rapamycin Complex 2/genetics MH - *Neoplasms/drug therapy/genetics/metabolism MH - Oleic Acids MH - Oxaloacetates MH - Phosphatidic Acids MH - Proto-Oncogene Proteins c-akt/metabolism MH - Transaminases/genetics PMC - PMC9586366 COIS- The authors have declared that no competing interests exist. EDAT- 2022/10/22 06:00 MHDA- 2022/10/26 06:00 PMCR- 2022/10/21 CRDT- 2022/10/21 13:36 PHST- 2022/08/05 00:00 [received] PHST- 2022/10/10 00:00 [accepted] PHST- 2022/10/21 13:36 [entrez] PHST- 2022/10/22 06:00 [pubmed] PHST- 2022/10/26 06:00 [medline] PHST- 2022/10/21 00:00 [pmc-release] AID - PONE-D-22-22032 [pii] AID - 10.1371/journal.pone.0276579 [doi] PST - epublish SO - PLoS One. 2022 Oct 21;17(10):e0276579. doi: 10.1371/journal.pone.0276579. eCollection 2022.