A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis
By Y. Zou, Michael J. Palte, A. Deik, Haoxin Li, J. Eaton, Wenyu Wang, Yuen-Yi Tseng, Rebecca Deasy, M. Kost-Alimova, V. Dancík and 10 more. Nature Communications, 2019
772 citations recorded by the source corpus.
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.
Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/bcc57fb0d4bd3179b8bfa5bc6905f8903dab292b
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Citations in the corpus
- Ferroptosis: mechanisms and links with diseases (2021, background): “Several studies have suggested that the sensitivity to GPx4 inhibitors varies greatly across different cell lines in ferroptosis.(121) To explore the possible additional regulatory pathways, CRISPR/ Cas9-based screens have been performed, and revealed that FSP1 is a previously unrecognized anti-ferr”
- Ferroptosis: molecular mechanisms and health implications (2020, background): “Unlike HIF1A, endothelial PAS domain protein 1 (EPAS1, also known as HIF2A) appears to promote ferroptosis in clear cell carcinoma cells through transcriptional upregulation of hypoxiainducible lipid droplet-associated (HILPDA/HIG2),(144) a regulator of enriched lipids that contains polyunsaturated ”
- The cell biology of ferroptosis (2024, positive): “Conversely, HILPDA depletion reduces ferroptosis sensitivity 138 .”
- Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “236 This evidence reveals the complex mechanisms through which hypoxia regulates ferroptosis in cancer and emphasizes the importance of targeting hypoxia signaling as a crucial approach in anticancer therapies.”
- Iron Metabolism in Ferroptosis (2020, background): “Stabilizing HIF1A by hypoxia or cobalt chloride inhibits ferroptosis (Yang et al., 2019), whereas endothelial PAS domain protein 1 (EPAS1/HIF2A) promotes ferroptosis in certain cancer cells (Zou et al., 2019).”
- Autophagy-Dependent Ferroptosis: Machinery and Regulation (2020, background): “In addition to HIF1A, endothelial PAS domain protein 1 (EPAS1/HIF2A) regulates ferroptosis in kidney cancer (Zou et al., 2019).”
- The interaction between ferroptosis and lipid metabolism in cancer (2020, background): “In addition, HIF-2 selectively enriches lipids that contain polyunsaturated fatty acyl side chains and induces a ferroptosissusceptible cell state, by activating the expression of hypoxiainducible, lipid droplet-associated protein (HILPDA).(61) Hence, upregulating SCD1 and FADS2, the genes involved ”