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Elesclomol induces copper-dependent ferroptosis in colorectal cancer cells via degradation of ATP7A.

ABSTRACT: Cancer cells reprogram their copper metabolism to adapt to adverse microenvironments, such as oxidative stress. The copper chelator elesclomol has been reported to have considerable anticancer efficacy, but the underlying mechanisms remain largely unknown. In this study, we found that elesclomol-mediated copper overload inhibits colorectal cancer (CRC) both in vitro and in vivo. Elesclomol alone promotes the degradation of the copper transporter copper-transporting ATPase 1 (ATP7A), which retards the proliferation of CRC cells. This property distinguishes it from several other copper chelators. Combinational treatment of elesclomol and copper leads to copper retention within mitochondria due to ATP7A loss, leading to reactive oxygen species accumulation, which in turn promotes the degradation of SLC7A11, thus further enhancing oxidative stress and consequent ferroptosis in CRC cells. This effect accounts for the robust antitumour activity of elesclomol against CRC, which can be reversed by the administration of antioxidants and ferroptosis inhibitors, as well as the overexpression of ATP7A. In summary, our findings indicate that elesclomol-induced copper chelation inhibits CRC by targeting ATP7A and regulating ferroptosis.

SUBMITTER: Gao W

PROVIDER: S-EPMC8637554 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Elesclomol induces copper-dependent ferroptosis in colorectal cancer cells via degradation of ATP7A.

Gao Wei W Huang Zhao Z Duan Jiufei J Nice Edouard C EC Lin Jie J Huang Canhua C

Molecular oncology 20210915 12

Cancer cells reprogram their copper metabolism to adapt to adverse microenvironments, such as oxidative stress. The copper chelator elesclomol has been reported to have considerable anticancer efficacy, but the underlying mechanisms remain largely unknown. In this study, we found that elesclomol-mediated copper overload inhibits colorectal cancer (CRC) both in vitro and in vivo. Elesclomol alone promotes the degradation of the copper transporter copper-transporting ATPase 1 (ATP7A), which retard ...[more]

PMID: 34390123

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Project description:Colorectal cancer is among the most frequently diagnosed cancers with high mortality rates and poses a serious threat to human health. Genistein (Gen) has been found to have anti-colorectal cancer effects, however, the molecular mechanisms by which genistein elicits its effects on colorectal cancer (CRC) cells have not been fully elucidated. In this study, we investigated the oxidative state of colorectal cancer cells during the antitumor action of Genistein and whether it can exert its antitumor effects through ferroptosis. Current research on the oxidative state of Genistein indicates that it exhibits both antioxidant and pro-oxidant properties. Different drug concentrations were applied to colorectal cancer cells, after which cell viability and key markers of ferroptosis, including reactive oxygen species (ROS), malondialdehyde (MDA), and Fe2+, were measured. We found that genistein significantly reduced the viability of colorectal cancer cells, and the expression of ferroptosis markers increased in a concentration-dependent manner. Subsequently, we treated cells with the ferroptosis inhibitor fer-1 in combination with genistein and observed a partial reversal of ferroptosis markers. These findings suggest that genistein exerts its antitumor effect by promoting iron-dependent oxidative damage-induced ferroptosis. To further elucidate the mechanism underlying ferroptosis modulation, we examined the protein and mRNA expression levels of the classical key ferroptosis molecules SLC7A11 and GPX4. We found that the expression levels of these molecules decreased, with GPX4 exhibiting a greater decrease. Overexpression of GPX4 reversed the pro-ferroptotic effect of genistein, indicating that genistein promotes ferroptosis occurrence by downregulating GPX4 expression. When the drug was applied to colorectal cancer cells, the expression of the transcription factor FoxO3 increased. Treatment of cells with the FoxO3 inhibitor JY-2 in combination with other drugs resulted in antagonism of ferroptosis markers. These findings suggest that genistein induces ferroptosis in colorectal cancer cells through the FoxO3/SLC7A11/GPX4 signaling pathway, thereby inhibiting tumor growth.

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Elesclomol induces copper-dependent ferroptosis in colorectal cancer cells via degradation of ATP7A.

Publications

Elesclomol induces copper-dependent ferroptosis in colorectal cancer cells via degradation of ATP7A.

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