The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma

Metabolic reprogramming is a prominent feature of clear cell renal cell carcinoma (ccRCC). Here we investigated metabolic dependencies in a panel of ccRCC cell lines using nutrient depletion, functional RNAi screening and inhibitor treatment. We found that ccRCC cells are highly sensitive to the dep...

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Vydáno v:	Oncogene Ročník 37; číslo 40; s. 5435 - 5450
Hlavní autoři:	Miess, Heike, Dankworth, Beatrice, Gouw, Arvin M., Rosenfeldt, Mathias, Schmitz, Werner, Jiang, Ming, Saunders, Becky, Howell, Michael, Downward, Julian, Felsher, Dean W., Peck, Barrie, Schulze, Almut
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 01.10.2018 Nature Publishing Group
Témata:	13/106 13/51 38/77 38/89 631/337/505 631/67/589/1588/1351 64/60 82/58 82/80 Amino acids Apoptosis Basic Helix-Loop-Helix Transcription Factors - metabolism Cancer Cancer cells Carcinoma Carcinoma, Renal Cell - pathology Care and treatment Cell Biology Cell Death Cell Line, Tumor Cell Proliferation Clear cell-type renal cell carcinoma Cysteine Cystine Development and progression Enzyme regulation Enzymes Epithelial cells Fatty acids Ferroptosis Gene silencing Genes Genetic aspects Glutamine Glutathione Glutathione - metabolism Glutathione Peroxidase - metabolism Health aspects Human Genetics Humans Hypoxia Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Internal Medicine Kidney cancer Kidney Neoplasms - pathology Lipid Metabolism Lipid Peroxidation Lipids Medical schools Medicine Medicine & Public Health Metabolism Mitochondria Myc protein Oncology Oxidation Oxidation-Reduction Oxidation-reduction reactions Oxidative metabolism Phosphorylation Renal cell carcinoma RNA interference RNA-mediated interference Tumors VHL protein
ISSN:	0950-9232, 1476-5594, 1476-5594
On-line přístup:	Získat plný text
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Popis
Shrnutí:	Metabolic reprogramming is a prominent feature of clear cell renal cell carcinoma (ccRCC). Here we investigated metabolic dependencies in a panel of ccRCC cell lines using nutrient depletion, functional RNAi screening and inhibitor treatment. We found that ccRCC cells are highly sensitive to the depletion of glutamine or cystine, two amino acids required for glutathione (GSH) synthesis. Moreover, silencing of enzymes of the GSH biosynthesis pathway or glutathione peroxidases, which depend on GSH for the removal of cellular hydroperoxides, selectively reduced viability of ccRCC cells but did not affect the growth of non-malignant renal epithelial cells. Inhibition of GSH synthesis triggered ferroptosis, an iron-dependent form of cell death associated with enhanced lipid peroxidation. VHL is a major tumour suppressor in ccRCC and loss of VHL leads to stabilisation of hypoxia inducible factors HIF-1α and HIF-2α. Restoration of functional VHL via exogenous expression of pVHL reverted ccRCC cells to an oxidative metabolism and rendered them insensitive to the induction of ferroptosis. VHL reconstituted cells also exhibited reduced lipid storage and higher expression of genes associated with oxidiative phosphorylation and fatty acid metabolism. Importantly, inhibition of β-oxidation or mitochondrial ATP-synthesis restored ferroptosis sensitivity in VHL reconstituted cells. We also found that inhibition of GSH synthesis blocked tumour growth in a MYC-dependent mouse model of renal cancer. Together, our data suggest that reduced fatty acid metabolism due to inhibition of β-oxidation renders renal cancer cells highly dependent on the GSH/GPX pathway to prevent lipid peroxidation and ferroptotic cell death.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 these authors contributed equally
ISSN:	0950-9232 1476-5594 1476-5594
DOI:	10.1038/s41388-018-0315-z