Solasonine promotes ferroptosis of hepatoma carcinoma cells via glutathione peroxidase 4-induced destruction of the glutathione redox system

Jin, Mingming; Shi, Chunzi; Li, Tian; Wu, Yue; Hu, Cheng; Huang, Gang

doi:10.1016/j.biopha.2020.110282

Cited by 100 publications

(78 citation statements)

References 24 publications

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“…In contrast, CBS overexpression confers ferroptosis resistance [66]. For GSS, one study reported that inhibiting GSS by solasonine, a compound isolated from Solanum melongena, elevates lipid ROS levels in HepG2 cells [67]. In the current study, we further uncovered that GSS is tightly regulated by RRM2, and dephosphorylation of RRM2 at T33 facilitates proteasome-mediated degradation of Diagnostic value of serum RRM2 in predicting liver cancer.…”

Section: Discussionmentioning

confidence: 50%

RRM2 protects against ferroptosis and is a tumor biomarker for liver cancer

et al. 2020

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Background Ferroptosis is the process of cell death triggered by lipid peroxides, and inhibition of glutathione (GSH) synthesis leads to ferroptosis. Liver cancer progression is closely linked to ferroptosis suppression. However, the mechanism by which inhibition of GSH synthesis suppresses potential ferroptosis of liver cancer cells and whether ferroptosis-related liver cancer biomarkers have a promising diagnostic value remain unknown. Methods Ribonucleotide reductase regulatory subunit M2 (RRM2) levels were measured using an enzyme linked immunosorbent assay (ELISA), quantitative RT-PCR (qPCR), immunoblotting (IB) and immunochemistry (IHC). Cell viability and cell death were measured by a CellTiter-Glo luminescent cell viability assay and staining with SYTOX Green followed by flow cytometry, respectively. Metabolites were measured using the indicated kits. The Interaction between glutathione synthetase (GSS) and RRM2 was measured using immunofluorescence (IF), co-immunoprecipitation (co-IP) and the proximal ligation assay (PLA). The diagnostic value was analyzed using the area under the receiver operating characteristic curve (AUC-ROC). Bioinformatics analysis was performed using the indicated database. Results RRM2 showed specifically elevated levels in liver cancer and inhibited ferroptosis by stimulating GSH synthesis via GSS. Mechanistically, phosphorylation of RRM2 at the Threonine 33 residue (T33) was maintained at normal levels to block the RRM2–GSS interaction and therefore protected RRM2 and GSS from further proteasome degradation. However, under ferroptotic stress, RRM2 was dephosphorylated at T33, thus the RRM2–GSS interaction was promoted. This resulted in the translocation of RRM2 and GSS to the proteasome for simultaneous degradation. Clinically, serum RRM2 was significantly associated with serum alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transpeptidase (γ-GT), albumin (ALB) and total bilirubin. The AUC-ROC for the combination of RRM2 with AFP was 0.947, with a sensitivity of 88.7% and a specificity of 97.0%, which indicates better diagnostic performance compared to either RRM2 or AFP alone. Conclusion RRM2 exerts an anti-ferroptotic role in liver cancer cells by sustaining GSH synthesis. Serum RRM2 will be useful as a biomarker to evaluate the degree to which ferroptosis is suppressed and improve diagnostic efficiency for liver cancer.

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Section: Discussionmentioning

confidence: 50%

RRM2 protects against ferroptosis and is a tumor biomarker for liver cancer

et al. 2020

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“…For various human cancers, dysregulation of the cell cycle is an important course of tumorigenesis and progression (37). Jin et al observed that solasonine induced a higher proportion of human HCC cells to accumulate in the G2/ M phase, which means solasonine caused cell cycle arrest in the G2/M phase (38). However, other studies have indicated that solasonine caused cell cycle arrest in the S phase, such as those by Wang et al (28) and Fekry et al (39).…”

Section: Discussionmentioning

confidence: 99%

Solasonine Suppresses the Proliferation of Acute Monocytic Leukemia Through the Activation of the AMPK/FOXO3A Axis

et al. 2021

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Solasonine, the main active ingredient of Solanum nigrum L., has been reported to exert extensive antitumor activity. However, the antitumor effects in acute monocytic leukemia and the exact mechanisms involved are unknown. In this study, we investigated the role of solasonine on inhibiting the progression of acute monocytic leukemia. Our findings showed that solasonine inhibited the proliferation of acute monocytic leukemic cell lines (THP-1 and MV4-11) in vitro. Solasonine promoted apoptosis and induced cell cycle arrest in the G2/M phase. Analysis of RNA-seq data suggested that solasonine correlated with increased expression of genes in the AMPK/FOXO3A pathway. Inhibition of AMPK with compound C followed by treatment with solasonine showed that solasonine reduced apoptosis, caused less cell cycle arrest, and inactivated the AMPK/FOXO3A axis in THP-1 and MV4-11 cells. Solasonine also inhibited tumor growth by the activation of the AMPK/FOXO3A axis. In conclusion, solasonine inhibited the progress of acute monocytic leukemia in vitro and in vivo and triggered the apoptosis and cell cycle arrest in the G2/M phase by upregulating the AMPK/FOXO3A pathway.

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“…A study found that the overexpression and knockdown of GPX4 can modulate the lethality of 12 ferroptosis inducers which proved that GPX4 was the important regulator of ferroptosis [34]. GSS is also associated with GSH, which inhibited elevated lipid ROS levels in HepG2 cells [35]. In addition, another study shown that ribonucleotide reductase regulatory subunit M2 (RRM2) inhibited ferroptosis by stimulating GSH synthesis via GSS in liver cancer [36].…”

Section: Discussionmentioning

confidence: 99%

A Novel Ferroptosis-related 6-Gene Signature for Overall Survival Prediction in Patients with Thyroid carcinoma

Wang¹,

Qiu²,

Shen³

2021

Preprint

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Background: Ferroptosis is a new form of regulated cell death (RCD) that plays a crucial role in the genesis and prognosis of tumor. Nevertheless, the relationship between ferroptosis and the prognosis of thyroid carcinoma (THCA) remains unclear and needs to be explored. Methods: By analyzing data from the THCA cohort in the TCGA database, ferroptosis-related differentially expressed genes (DEGs) with prognostic value were identified, which were used to establish a prognostic signature based on Lasso-penalized Cox regression analysis. Then, the model was testified with Kaplan-Meier survival, Cox regression and receiver operating characteristic (ROC) analyses based on overall survival (OS). Finally, DEGs between the low-risk and high-risk groups were identified and used to conduct GO enrichment analysis, KEGG pathways analysis and immune infiltration analysis.Results: A 6-gene signature was constructed which including DPP4, GPX4, GSS, HMGCR, TFRC and PGD. The area under the curve (AUC) were 0.890 (1 year), 0.863 (2 years) and 0.883 (3 years) which validated the prominent predictive capacity of the model. Multivariate Cox regression certified the model as a prognostic-related independent predictor for OS.Conclusion: In this study, we established an innovative prognostic signature of 6 ferroptosis-related genes which can be as a prognostic-related independent predictor for OS in THCA, while the potential mechanisms was still unclear and needed further exploration.

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Solasonine promotes ferroptosis of hepatoma carcinoma cells via glutathione peroxidase 4-induced destruction of the glutathione redox system

Cited by 100 publications

References 24 publications

RRM2 protects against ferroptosis and is a tumor biomarker for liver cancer

RRM2 protects against ferroptosis and is a tumor biomarker for liver cancer

Solasonine Suppresses the Proliferation of Acute Monocytic Leukemia Through the Activation of the AMPK/FOXO3A Axis

A Novel Ferroptosis-related 6-Gene Signature for Overall Survival Prediction in Patients with Thyroid carcinoma

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