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

Autor: Green YS; University of Utah, Salt Lake City, UT, 84112, USA., Ferreira Dos Santos MC; Kuda Therapeutics, Inc, Salt Lake City, UT, 84103, USA., Fuja DG; University of Utah, Salt Lake City, UT, 84112, USA., Reichert EC; University of Utah, Salt Lake City, UT, 84112, USA., Campos AR; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA., Cowman SJ; University of Utah, Salt Lake City, UT, 84112, USA., Acuña Pilarte K; University of Utah, Salt Lake City, UT, 84112, USA., Kohan J; ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, 84108, USA., Tripp SR; ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, 84108, USA., Leibold EA; University of Utah, Salt Lake City, UT, 84112, USA., Sirohi D; ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, 84108, USA.; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA., Agarwal N; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA., Liu X; Kuda Therapeutics, Inc, Salt Lake City, UT, 84103, USA., Koh MY; University of Utah, Salt Lake City, UT, 84112, USA. mei.koh@utah.edu.; Kuda Therapeutics, Inc, Salt Lake City, UT, 84103, USA. mei.koh@utah.edu.; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA. mei.koh@utah.edu.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2022 Oct; Vol. 41 (42), pp. 4709-4723. Date of Electronic Publication: 2022 Sep 12.
DOI: 10.1038/s41388-022-02460-1
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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