ISCA2 inhibition decreases HIF and induces ferroptosis in clear cell renal carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is typically initiated by inactivation of the von Hippel Lindau (VHL) gene, which results in the constitutive activation of the hypoxia inducible factors, HIF-1α and HIF-2α. Using a high throughput screen, we identify novel compounds that decrease HIF-1/2α levels and induce ferroptosis by targeting Iron Sulfur Cluster Assembly 2 (ISCA2), a component of the late mitochondrial Iron Sulfur Cluster (L-ISC) assembly complex. ISCA2 inhibition either pharmacologically or using siRNA decreases HIF-2α protein levels by blocking iron-responsive element (IRE)-dependent translation, and at higher concentrations, also decreases HIF-1α translation through unknown mechanisms. Additionally, ISCA2 inhibition triggers the iron starvation response, resulting in iron/metals overload and death via ferroptosis. ISCA2 levels are decreased in ccRCC compared to normal kidney, and decreased ISCA2 levels are associated with pVHL loss and with sensitivity to ferroptosis induced by ISCA2 inhibition. Strikingly, pharmacological inhibition of ISCA2 using an orally available ISCA2 inhibitor significantly reduced ccRCC xenograft growth in vivo, decreased HIF-α levels and increased lipid peroxidation, suggesting increased ferroptosis in vivo. Thus, the targeting of ISCA2 may be a promising therapeutic strategy to inhibit HIF-1/2α and to induce ferroptosis in pVHL deficient cells.

Ferroptosis Regulated by Hypoxia in Cells

“…It was also reported that HIF-1α and HIF-2α have different targets: HIF-1α regulates most of the glycolytic-related genes, whereas HIF-2α selectively regulates many iron-regulatory genes [ 175 , 176 ]. Consistently, the abovementioned studies showed that HIF-2α inhibits ferroptosis through its direct targets involved in iron metabolism, such as FTMT , in both tumor and normal cells [ 102 , 112 ]. However, it is also reported that HIF-1α regulates iron metabolism directly through transcriptionally regulation of its targets, such as TFRC and DMT1 [ 120 ], as well as indirectly through some other targets, such as CA9 [ 103 ].…”

“…In clear cell renal cell carcinoma (ccRCC), both HIF-1α and HIF-2α are stabilized by VHL loss, leading to the decrease in ferroptosis sensitivity to erastin or BSO via fatty acid β-oxidation and mitochondrial ATP-synthesis [ 101 ]. A recent study on clear cell renal cell carcinoma showed that the iron sulfur cluster assembly 2 (ISCA2), a component of the late mitochondrial iron sulfur cluster assembly complex, was induced by hypoxia (1% O 2 ) to promote HIF-1α/HIF-2α translation, leading to the inhibition of iron overload and erastin- or RSL3-induced ferroptosis [ 102 ].…”

Novel Insight into Ferroptosis in Kidney Diseases

“…STEAP3 influences ferroptosis and RCC progression via the p53/xCT pathway [63]. Studies have demonstrated that suppression of ISCA2 reduces HIF and causes ferroptosis in ccRCC [127]. Kerimoglu et al [128] revealed that the cyst(e)inase-rapamycin combination caused ferroptosis in both in vitro and in vivo models of hereditary leiomyomatosis and RCC.…”

Regulatory roles of ferroptosis-related non-coding RNAs and their research progress in urological malignancies

“…Despite the availability of multiple therapeutic strategies, it is still necessary to explore novel therapeutic approaches and tumor markers. Recent studies have shown that tumor cells are more sensitive to ferroptosis than normal cells, Frontiers in Genetics frontiersin.org particularly renal cancer cells (Yang et al, 2014;Zou et al, 2019;Green et al, 2022). Therefore, in-depth studies on the role of ferroptosis-associated ncRNAs in kidney cancer may be meaningful for the discovery of novel tumor diagnostic markers and potential therapeutic strategies (Zhang et al, 2019;Lei et al, 2022;Li et al, 2022;Zhu et al, 2022).…”