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이혜민Hyemin Lee

University of Texas MD Anderson Cancer Center

Nat. Commun., Jan 02 2024, 15 (1) | https://doi.org/10.1038/s41467-023-44412-7 Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance

Hyemin Lee ¹, Amber Horbath ¹, Lavanya Kondiparthi ^{2 3}, Jitendra Kumar Meena ⁴, Guang Lei¹, Shayani Dasgupta¹, Xiaoguang Liu¹, Li Zhuang ¹, Pranavi Koppula ^{1 5}, Mi Li ¹, Iqbal Mahmud ⁶, Bo Wei ⁶, Philip L Lorenzi ⁶, Khandan Keyomarsi ^{1 5}, Masha V Poyurovsky ^{2 7}, Kellen Olszewski ^{2 8}, Boyi Gan ^{9 10 11 *}

¹Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

²Kadmon Corporation, New York, NY, 10016, USA.

³Sanofi US, Cambridge, MA, 02139, USA.

⁴Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.

⁵The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, 77030, USA.

⁶Metabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

⁷PMV Pharmaceuticals, Princeton, NJ, 08540, USA.

⁸Carl Icahn Labs, Princeton University, Princeton, NJ, 08544, USA.

⁹Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

¹⁰The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, 77030, USA.

¹¹Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

^*Corresponding author: correspondence to Boyi Gan

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.

논문정보

형식Research article
게재일2024년 01월 (BRIC 등록일 2024-01-05)
연구진국외 연구진
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