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Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance

Author

Listed:
  • Hyemin Lee

    (The University of Texas MD Anderson Cancer Center)

  • Amber Horbath

    (The University of Texas MD Anderson Cancer Center)

  • Lavanya Kondiparthi

    (Kadmon Corporation
    Sanofi US)

  • Jitendra Kumar Meena

    (Baylor College of Medicine)

  • Guang Lei

    (The University of Texas MD Anderson Cancer Center)

  • Shayani Dasgupta

    (The University of Texas MD Anderson Cancer Center)

  • Xiaoguang Liu

    (The University of Texas MD Anderson Cancer Center)

  • Li Zhuang

    (The University of Texas MD Anderson Cancer Center)

  • Pranavi Koppula

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences)

  • Mi Li

    (The University of Texas MD Anderson Cancer Center)

  • Iqbal Mahmud

    (The University of Texas MD Anderson Cancer Center)

  • Bo Wei

    (The University of Texas MD Anderson Cancer Center)

  • Philip L. Lorenzi

    (The University of Texas MD Anderson Cancer Center)

  • Khandan Keyomarsi

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences)

  • Masha V. Poyurovsky

    (Kadmon Corporation
    PMV Pharmaceuticals)

  • Kellen Olszewski

    (Kadmon Corporation
    Carl Icahn Labs, Princeton University)

  • Boyi Gan

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences
    The University of Texas MD Anderson Cancer Center)

Abstract

How cells coordinate cell cycling with cell survival and death remains incompletely understood. Here, we show that cell cycle arrest has a potent suppressive effect on ferroptosis, a form of regulated cell death induced by overwhelming lipid peroxidation at cellular membranes. Mechanistically, cell cycle arrest induces diacylglycerol acyltransferase (DGAT)–dependent lipid droplet formation to sequester excessive polyunsaturated fatty acids (PUFAs) that accumulate in arrested cells in triacylglycerols (TAGs), resulting in ferroptosis suppression. Consequently, DGAT inhibition orchestrates a reshuffling of PUFAs from TAGs to phospholipids and re-sensitizes arrested cells to ferroptosis. We show that some slow-cycling antimitotic drug–resistant cancer cells, such as 5-fluorouracil–resistant cells, have accumulation of lipid droplets and that combined treatment with ferroptosis inducers and DGAT inhibitors effectively suppresses the growth of 5-fluorouracil–resistant tumors by inducing ferroptosis. Together, these results reveal a role for cell cycle arrest in driving ferroptosis resistance and suggest a ferroptosis-inducing therapeutic strategy to target slow-cycling therapy-resistant cancers.

Suggested Citation

  • Hyemin Lee & Amber Horbath & Lavanya Kondiparthi & Jitendra Kumar Meena & Guang Lei & Shayani Dasgupta & Xiaoguang Liu & Li Zhuang & Pranavi Koppula & Mi Li & Iqbal Mahmud & Bo Wei & Philip L. Lorenzi, 2024. "Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44412-7
    DOI: 10.1038/s41467-023-44412-7
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