Hypersensitivity to ferroptosis in chromophobe RCC is mediated by a glutathione metabolic dependency and cystine import via solute carrier family 7 member 11

Abstract

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.

CircZBTB44 promotes renal carcinoma progression by stabilizing HK3 mRNA structure

“…Rescue assays revealed that circZBTB44 promoted RCC malignancy and M2 polarization of macrophages by up-regulating HK3. In addition, the solute carrier (SLC) transporters are promising targets for the treatment of cancer [ 47 ], including RCC [ 48 ]. Considering the metabolic gatekeeper role of SLC transporters [ 49 ] and the significant involvement of HK3 in metabolic reprograming, we speculate that HK3 regulation and/or function is also related with certain SLC transporters in RCC.…”

Novel Insight into Ferroptosis in Kidney Diseases

“…Moreover, fumarate hydratase inactivation is synthetically deadly with ferroptosis induction in hereditary leiomyomatosis and RCC [86]. In chromophobic RCC, hypersensitivity to ferroptosis is mediated by glutathione metabolic depend-ence and cystine import via solute carrier family 7 member 11 [87].…”

Research Progress on Ferroptosis as a Therapeutic Strategy in Renal Cell Carcinoma

“…As an important antioxidant in the cell, GSH can neutralize lipid peroxide products. The γ-glutamyltransferase (GGT1) can catalyze the extracellular GSH lysis, providing cysteine for GSH generated in the cell, and is a part of the GSH salvage pathway [30]. Bansal et al [31] demonstrate that GGT1 levels in the ccRCC cell line (786-O and RCC10) increased significantly, and GGT1 could prevent tumor cell from lipid peroxidation to ferroptosis by promoting GSH synthesis facilitating tumor cell proliferation and metastasis.…”