Curcumin derivative NL01 induces ferroptosis in ovarian cancer cells via HCAR1/MCT1 signaling

Abstract

Objective: Curcumin has been shown to have anti-tumor proliferative properties, but its clinical application is limited by its low bioavailability, etc. Derivatives of curcumin have been developed and tested to improve its therapeutic efficacy. Derivative NL01 could induce ferroptosis through the HCAR1/MCT1 pathway.

Method: CCK-8 was used to detect curcumin and derivative IC₅₀, crystalline violet staining was used to detect the proliferation inhibition effect of NL01 in ovarian cancer, western blot and qPCR were used to detect downstream related molecular expression changes, Transwell and survival curve assays were used to detect malignant phenotypic.

Results: NL01 inhibited cell growth of Anglne and HO8910PM ovarian cancer cells by 13 times more potent than curcumin and induced ferroptosis of these two cells. we found that NL01 was able to reduce the expression of HCAR1/MCT1 and activate the AMPK signaling pathway, which in turn induced cellular ferroptosis via SREBP1 pathway. Knock-down HCAR1 expression revealed similar phenotype and pathway alterations to NL01 treatment. HCAR1 overexpression promoted a malignant phenotype and resistance to cisplatin in both cancer cells, whereas knockdown of HCAR1 showed the opposite phenotype. Subcutaneous transplantation tumor experiments in nude mice also showed that NL01 induced iron death and inhibited ovarian cancer proliferation. Further study showed that NL01 promoted the downregulation of GPX4 expression, which is related to ferroptosis, and that addition of ferrostatin-1 partially reversed NL01-mediated inhibition of the growth of two cell lines.

Conclusion: NL01 exhibits better anti-tumor growth properties than curcumin, and NL01 induces ferroptosis in ovarian cancer cells.

Keywords: Curcumin derivative; Ferroptosis; HCAR1; Lactate uptake; MCT1.