ArticleOncogene2015
Blocking anaplerotic entry of glutamine into the TCA cycle sensitizes K-Ras mutant cancer cells to cytotoxic drugs.
Article in Oncogene, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 66 citations in OpenAlex.
- Glutamine signaling specifically activates c-Myc and Mcl-1 to facilitate cancer cell proliferation and survival.Protein & cell · 2025Article
- Beyond the tumor: Enhancing pancreatic cancer therapy through glutamine metabolism and innovative drug delivery.Journal of cell communication and signaling · 2025Review
- KRASCell reports. Medicine · 2025Article
- Mitochondrial-cytochrome c oxidase II promotes glutaminolysis to sustain tumor cell survival upon glucose deprivation.Nature communications · 2025Article
- Fuel for thought: targeting metabolism in lung cancer.Translational lung cancer research · 2024Review
- NF1 deficiency drives metabolic reprogramming in ER+ breast cancer.Molecular metabolism · 2024Article
- Glutamine addiction in tumor cell: oncogene regulation and clinical treatment.Cell communication and signaling : CCS · 2024Review
- SLC25A21 downregulation promotes KRAS-mutant colorectal cancer progression by increasing glutamine anaplerosis.JCI insight · 2023Article
- The mitochondrial CabioRxiv : the preprint server for biology · 2023Article
- Targeting RAS mutants in malignancies: successes, failures, and reasons for hope.Cancer communications (London, England) · 2023Review
- The mitochondrial CaFrontiers in cell and developmental biology · 2023Article
- SIRT4 functions as a tumor suppressor during prostate cancer by inducing apoptosis and inhibiting glutamine metabolism.Scientific reports · 2022Article
- Inhibiting glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells.PloS one · 2022Article
- Turbulence of glutamine metabolism in pan-cancer prognosis and immune microenvironment.Frontiers in oncology · 2022Article
- KRAS mutation: from undruggable to druggable in cancer.Signal transduction and targeted therapy · 2021Review
- More Than Meets the Eye Regarding Cancer Metabolism.International journal of molecular sciences · 2021Review
- RSF1 in cancer: interactions and functions.Cancer cell international · 2021Review
- The Metabolic Landscape of RAS-Driven Cancers from biology to therapy.Nature cancer · 2021Review
- Mechanisms of Resistance to KRASCancers · 2021Review
- Glutamine reliance in cell metabolism.Experimental & molecular medicine · 2020Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.