SLC12A5 promotes hepatocellular carcinoma growth and ferroptosis resistance by inducing ER stress and cystine transport changes. (16th January 2023)

• Record Type: Journal Article
• Authors: Tong, Qing; Qin, Wei; Li, Zheng‐Hao; Liu, Chun; Wang, Zi‐Cheng; Chu, Yuan; Xu, Xun‐Di
• Is Part Of: Cancer medicine. Volume 12:Number 7(2023)
• Page Start: 8526
• Page End: 8541
• Publication Date: 2023-01-16
• Subjects: cystine transport -- endoplasmic reticulum stress -- ferroptosis -- hepatocellular carcinoma -- SLC12A5; 616.994005
• DOI: 10.1002/cam4.5605
• Languages: English
• ISSNs: 2045-7634

Abstract

Abstract: Background: Hepatocellular carcinoma (HCC) has a poor prognosis and new effective treatments are needed. SLC12A5 plays important roles in multiple complex pathological states and is overexpressed in a variety of malignancies. However, the effects of SLC12A5 in HCC have not been determined. Methods: SLC12A5 expression was assessed by immunostaining and western blotting. A cell viability assay was used to detect cell proliferation. Flow cytometry was used to evaluate the intracellular calcium concentration and cell cycle. Ferroptosis was detected by transmission electron microscopy, lipid peroxidation, and glutathione assays. Subcutaneous tumor formation experiments were used to validate the tumorigenic effect of SLC12A5 in vivo. RNA‐seq was used to evaluate the molecular mechanisms underlying the effects of SLC12A5. The therapeutic efficacy of targeting SLC12A5 was assessed in a patient‐derived xenograft (PDX) model. Results: High SLC12A5 expression was strongly associated with a poor clinical prognosis and promoted HCC growth. Mechanistically, SLC12A5 promoted ER stress to enhance calcium release and upregulated PNCK expression levels. Concomitantly, PNCK was significantly activated by calcium ions released from the ER. PNCK activated and induced the phosphorylation of PI3K/AKT/mTOR pathway components. Furthermore, SLC12A5 inhibited ferroptosis in HCC by upregulating the expression of xCT, a cystine transporter. Conclusion: High SLC12A5 levels were correlated with a poor prognosis, promoted tumorigenesis, and inhibited ferroptosis in HCC. These findings suggested that SLC12A5 is a therapeutic target and provide insight into the link between ER stress and ferroptosis in HCC. Abstract : Ion homeostasis plays a critical role in liver damage and the initiation and progression of hepatocellular carcinoma (HCC). We showed that SLC12A5 (K+‐Cl‐ cotransporter) is overexpressed in HCC and predicts poor prognosis. SLC12A5 promoted ER stress and upregulated PNCK expression levels. PNCK induced phosphorylation of the PI3K/AKT/mTOR pathway components. Furthermore, SLC12A5 inhibited ferroptosis in HCC by upregulating the expression of xCT. SLC12A5 antagonist VU0240551 has translational potential for HCC treatment.