title: Blocking anaplerotic entry of glutamine into the TCA cycle sensitizes K-Ras mutant cancer cells to cytotoxic drugs.
abstract: Cancer cells undergo a metabolic transformation that allows for increased anabolic demands, wherein glycolytic and tricarboxylic acid (TCA) cycle intermediates are shunted away for the synthesis of biological molecules required for cell growth and division. One of the key shunts is the exit of citrate from the mitochondria and the TCA cycle for the generation of cytosolic acetyl-coenzyme A that can be used for fatty acid and cholesterol biosynthesis. With the loss of mitochondrial citrate, cancer cells rely on the 'conditionally essential' amino acid glutamine (Q) as an anaplerotic carbon source for TCA cycle intermediates. Although Q deprivation causes G1 cell cycle arrest in non-transformed cells, its impact on the cancer cell cycle is not well characterized. We report here a correlation between bypass of the Q-dependent G1 checkpoint and cancer cells harboring K-Ras mutations. Instead of arresting in G1 in response to Q-deprivation, K-Ras-driven cancer cells arrest in either S- or G2/M-phase. Inhibition of K-Ras effector pathways was able to revert cells to G1 arrest upon Q deprivation. Blocking anaplerotic utilization of Q mimicked Q deprivation--causing S- and G2/M-phase arrest in K-Ras mutant cancer cells. Significantly, Q deprivation or suppression of anaplerotic Q utilization created synthetic lethality to the cell cycle phase-specific cytotoxic drugs, capecitabine and paclitaxel. These data suggest that disabling of the G1 Q checkpoint could represent a novel vulnerability of cancer cells harboring K-Ras and possibly other mutations that disable the Q-dependent checkpoint.
authors.affiliation: Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Saqcena
authors.affiliation: Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mukhopadhyay
authors.affiliation: Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Hosny
authors.affiliation: Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Alhamed
authors.affiliation: Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Chatterjee
authors.affiliation: Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Foster
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000069287:Capecitabine; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle / Q000187:drug effects* / Q000235:genetics; D003603:Cytotoxins / Q000494:pharmacology*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D005973:Glutamine / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D003603:Cytotoxins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D005973:Glutamine; D003841:Deoxycytidine; D000069287:Capecitabine; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D017239:Paclitaxel; D005472:Fluorouracil