A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis
| Autor: | Wenyu Wang, Vasanthi S. Viswanathan, Sabina Signoretti, Clary B. Clish, Michael J. Palte, Jesse S. Boehm, Elizaveta S. Leshchiner, John G. Doench, Bridget K. Wagner, Vlado Dančík, Amy Deik, Toni K. Choueiri, John K. Eaton, Haoxin Li, Yilong Zou, Maria Kost-Alimova, Stuart L. Schreiber, Yuen-Yi Tseng, Rebecca Deasy, Paul A. Clemons |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Cell General Physics and Astronomy Apoptosis 02 engineering and technology GPX4 Lipid peroxidation chemistry.chemical_compound Gene Knockout Techniques RNA interference Basic Helix-Loop-Helix Transcription Factors Phospholipid-hydroperoxide glutathione peroxidase lcsh:Science Multidisciplinary Middle Aged 021001 nanoscience & nanotechnology Kidney Neoplasms 3. Good health Neoplasm Proteins Gene Expression Regulation Neoplastic medicine.anatomical_structure Female RNA Interference lipids (amino acids peptides and proteins) 0210 nano-technology Iron Science Mice Nude Biology General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Cell Line Tumor medicine Animals Humans Carcinoma Renal Cell Aged Glutathione Peroxidase Gene Expression Profiling HEK 293 cells General Chemistry Phospholipid Hydroperoxide Glutathione Peroxidase Xenograft Model Antitumor Assays Gene expression profiling 030104 developmental biology HEK293 Cells chemistry Cancer cell Cancer research lcsh:Q Lipid Peroxidation CRISPR-Cas Systems |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-13 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | Clear-cell carcinomas (CCCs) are a histological group of highly aggressive malignancies commonly originating in the kidney and ovary. CCCs are distinguished by aberrant lipid and glycogen accumulation and are refractory to a broad range of anti-cancer therapies. Here we identify an intrinsic vulnerability to ferroptosis associated with the unique metabolic state in CCCs. This vulnerability transcends lineage and genetic landscape, and can be exploited by inhibiting glutathione peroxidase 4 (GPX4) with small-molecules. Using CRISPR screening and lipidomic profiling, we identify the hypoxia-inducible factor (HIF) pathway as a driver of this vulnerability. In renal CCCs, HIF-2α selectively enriches polyunsaturated lipids, the rate-limiting substrates for lipid peroxidation, by activating the expression of hypoxia-inducible, lipid droplet-associated protein (HILPDA). Our study suggests targeting GPX4 as a therapeutic opportunity in CCCs, and highlights that therapeutic approaches can be identified on the basis of cell states manifested by morphological and metabolic features in hard-to-treat cancers. Clear-cell carcinomas are aggressive tumours characterised by high accumulation of lipids and glycogen. Here, the authors report that these cancers have a common vulnerability to GPX4 inhibition-induced ferroptosis and using CRISPR screen and lipodomic profiling, they identify HIF-2α- HILPDA axis promotes ferroptosis via enrichment of PUFA lipids. |
| Databáze: | OpenAIRE |
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