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. 2022 Jan 30:809:145992.
doi: 10.1016/j.gene.2021.145992. Epub 2021 Oct 11.

Everolimus accelerates Erastin and RSL3-induced ferroptosis in renal cell carcinoma

Wang Yangyun  1 , Shi Guowei  1 , Shi Shufen  2 , Yao Jie  3 , Yu Rui  3 , Ren Yu  4
Affiliations

Everolimus accelerates Erastin and RSL3-induced ferroptosis in renal cell carcinoma

Wang Yangyun et al. Gene. .

Abstract

Renal cell carcinoma (RCC) is a common type of urological cancer and is often diagnosed at an advanced stage. Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), is used as second-line therapy for sorafenib- or sunitinib-refractory metastatic RCC. However, the clinical benefits of Everolimus are often hampered by drug resistance. Ferroptosis is a novel form of regulated cell death that has recently been implicated in the development and therapeutic responses to different cancers. RSL3 ((1S,3R)-RSL3) and Erastin are two experimental compounds that can induce ferroptosis. In the present study, we evaluated the anti-tumor effects of Everolimus in combination with RSL3 or Erastin in RCC. Everolimus and RSL3/Erastin could synergistically inhibit the viability and induce ferroptosis in RCC cells. Mechanistically, the inhibition of the mTOR-4EBP1 axis was found to be essential for the synergistic effects of Everolimus and RSL3/Erastin. Moreover, the forced expression of GPX4 abrogated ferroptosis induced by the combined treatment of Everolimus and RSL3/Erastin. Taken together, these results demonstrated that Everolimus in combination with RSL3/Erastin is a promising therapeutic option for RCC treatment and it may also help to overcome the limitation in clinical applicability of Everolimus.

Keywords: Erastin; Everolimus; Ferroptosis; RSL3; Renal cell carcinoma; mTOR.

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