Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance

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, Khandan Keyomarsi, Masha V. Poyurovsky, Kellen Olszewski and Boyi Gan ()
Additional contact information
Hyemin Lee: The University of Texas MD Anderson Cancer Center
Amber Horbath: The University of Texas MD Anderson Cancer Center
Lavanya Kondiparthi: Kadmon Corporation
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
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
Masha V. Poyurovsky: Kadmon Corporation
Kellen Olszewski: Kadmon Corporation
Boyi Gan: The University of Texas MD Anderson Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-023-44412-7

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