Hypersensitivity to ferroptosis in chromophobe RCC is mediated by a glutathione metabolic dependency and cystine import via solute carrier family 7 member 11.
Long ZhangCharbel S HobeikaDamir KhabibullinDeyang YuHarilaos FilippakisMichel AlchoueiryYan TangHilaire C LamPeter TsvetkovGeorge GeorgiouCandice LambEverett M StonePere PuigserverCarmen PrioloElizabeth P HenskePublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
Chromophobe (Ch) renal cell carcinoma (RCC) arises from the intercalated cell in the distal nephron. There are no proven treatments for metastatic ChRCC. A distinguishing characteristic of ChRCC is strikingly high levels of reduced (GSH) and oxidized (GSSG) glutathione. Here, we demonstrate that ChRCC-derived cells exhibit higher sensitivity to ferroptotic inducers compared with clear-cell RCC. ChRCC-derived cells are critically dependent on cystine via the cystine/glutamate antiporter xCT to maintain high levels of glutathione, making them sensitive to inhibitors of cystine uptake and cyst(e)inase. Gamma-glutamyl transferase 1 (GGT1), a key enzyme in glutathione homeostasis, is markedly suppressed in ChRCC relative to normal kidney. Importantly, GGT1 overexpression inhibits the proliferation of ChRCC cells in vitro and in vivo, suppresses cystine uptake, and decreases levels of GSH and GSSG. Collectively, these data identify ferroptosis as a metabolic vulnerability in ChRCC, providing a potential avenue for targeted therapy for these distinctive tumors.
Keyphrases
- renal cell carcinoma
- induced apoptosis
- cell cycle arrest
- cell death
- signaling pathway
- squamous cell carcinoma
- endoplasmic reticulum stress
- small cell lung cancer
- stem cells
- cell therapy
- bone marrow
- oxidative stress
- mesenchymal stem cells
- minimally invasive
- fluorescent probe
- clear cell
- big data
- deep learning
- risk assessment
- electronic health record