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Blocking anaplerotic entry of glutamine into the TCA cycle sensitizes K-Ras mutant cancer cells to cytotoxic drugs

Oncogene volume 34, pages 2672–2680 (2015)Cite this article

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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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Acknowledgements

This study was supported by the National Institute of Health grant R01-CA046677 and a pilot project award from the Research Centers in Minority Institutions award RP-03037 from the National Center for Research Resources of the National Institute of Health.

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Author notes

  1. M Saqcena

    Present address: 3Current address: Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.,

  2. M Saqcena and S Mukhopadhyay: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Sciences, Hunter College of the City University of New York, New York, NY, USA

    M Saqcena, S Mukhopadhyay, C Hosny, A Alhamed, A Chatterjee & D A Foster

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  1. M Saqcena
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  2. S Mukhopadhyay
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  6. D A Foster
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Correspondence to D A Foster.

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Saqcena, M., Mukhopadhyay, S., Hosny, C. et al. Blocking anaplerotic entry of glutamine into the TCA cycle sensitizes K-Ras mutant cancer cells to cytotoxic drugs. Oncogene 34, 2672–2680 (2015). https://doi.org/10.1038/onc.2014.207

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