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. ISCA2 inhibition also 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 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.

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“…The inhibition of ISCA2 can significantly reduce the xenograft growth of clear cell renal cell carcinoma. Mechanistically, the suppression of ISCA2 both decreases HIF-α levels and induces ferroptosis through triggering singal pathways that does not rely on ISCA2’s role in mitochondrial [4Fe-4S] assembly ( Green et al, 2022 ), indicating that ISCA2 may be one of the potential regulators of HNSC progression.…”

“…DLAT can catalyze the conversion of pyruvate into Acetyl CoA, promote oxidative phosphorylation, ATP generation and catabolic reactions, which are important in the development of cancer ( Goh et al, 2015 ). In addation, CAT ( Galasso et al, 2021 ), POLE ( Bellido et al, 2016 ), NTHL1 ( Magrin et al, 2021 ), ATP7B ( Li et al, 2017 ), ISCA2 ( Weiler et al, 2020 ; Green et al, 2022 ), NDUFA1 ( Mamelak et al, 2005 ) and NDUFB2( Shan et al, 2020 ) have also been reported to play a key role in the development of cancers. The combination of multi-genes signature and clinical characters can improve the predictive ability of prognosis for cancer patients ( Yang et al, 2021 ).…”