Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance
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. Mechanistical...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44412-7 |
| _version_ | 1827388340683407360 |
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| author | 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 Boyi Gan |
| author_facet | 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 Boyi Gan |
| author_sort | Hyemin Lee |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T16:17:28Z |
| format | Article |
| id | doaj.art-8a9b82a867e747468ec49d729f1351db |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T16:17:28Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-8a9b82a867e747468ec49d729f1351db2024-01-07T12:32:16ZengNature PortfolioNature Communications2041-17232024-01-0115111310.1038/s41467-023-44412-7Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistanceHyemin Lee0Amber Horbath1Lavanya Kondiparthi2Jitendra Kumar Meena3Guang Lei4Shayani Dasgupta5Xiaoguang Liu6Li Zhuang7Pranavi Koppula8Mi Li9Iqbal Mahmud10Bo Wei11Philip L. Lorenzi12Khandan Keyomarsi13Masha V. Poyurovsky14Kellen Olszewski15Boyi Gan16Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterKadmon CorporationVerna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of MedicineDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterMetabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterMetabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterMetabolomics Core Facility, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer CenterDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterKadmon CorporationKadmon CorporationDepartment of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer CenterAbstract 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.https://doi.org/10.1038/s41467-023-44412-7 |
| spellingShingle | 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 Boyi Gan Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance Nature Communications |
| title | Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance |
| title_full | Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance |
| title_fullStr | Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance |
| title_full_unstemmed | Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance |
| title_short | Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance |
| title_sort | cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance |
| url | https://doi.org/10.1038/s41467-023-44412-7 |
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