Targeted Manganese doped silica nano GSH-cleaner for treatment of Liver Cancer by destroying the intracellular redox homeostasis

Tang, Hongxia; Li, Chaoqun; Zhang, Yue; Zheng, Hua; Cheng, Ying; Zhu, Jingjing; Chen, Xiaojie; Zhu, Zhihong; Piao, Ji-Gang; Li, Fanzhu

doi:10.7150/thno.46771

Cited by 103 publications

(70 citation statements)

References 48 publications

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“…GSH is one of the most important antioxidants and protects cells against lipid peroxide damage [ 38 , 61 ]. By utilizing GSH, ferroptosis is antagonized because lipid peroxides are reduced to their corresponding alcohols [ 9 , 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…By utilizing GSH, ferroptosis is antagonized because lipid peroxides are reduced to their corresponding alcohols [ 9 , 11 ]. It is also not difficult to understand that, exhausting GSH is a potential way to trigger ferroptosis [ 38 , 62 , 63 ]. GSH can be synthesized from three critical amino acids: cysteine, glutamate and glycine [ 64 , 65 ].…”

Section: Discussionmentioning

confidence: 99%

“…RRM2 antagonizes sorafenib, an FDA-approved multikinase inhibitor, to treat liver cancer, possibly due to its function to partially rescue liver cancer cells from sorafenib-induced long-term cytotoxicity [ 37 ]. Recently, the roles of sorafenib in triggering ferroptosis have been established in liver cancer cells [ 38 , 39 ]. However, whether and how RRM2 protects liver cancer cells against ferroptosis is still not known.…”

Section: Introductionmentioning

confidence: 99%

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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: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…ROS measurements further supported this conclusion. Studies have shown that oxidative stress is closely associated with apoptosis, and if the ability of cells to resist oxidative stress is diminished, intracellular ROS increase and lead to cell apoptosis [ 25 – 28 ]. Western blotting was used to detect the expression of apoptosis-associated proteins.…”

Section: Discussionmentioning

confidence: 99%

Vascular endothelial cell-secreted exosomes facilitate osteoarthritis pathogenesis by promoting chondrocyte apoptosis

Yang

Zheng

et al. 2021

Aging

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Exosomes are major mediators of cell-to-cell communication, and are involved in many physiological and pathological processes. Recently, the roles of exosomes in osteoarthritis (OA) and their therapeutic potential have received increasing attention. Exosomes derived from vascular endothelial cells have been confirmed to participate in the occurrence and development of numerous diseases; however, their effects in OA have not been reported. Here, we demonstrated the roles of exosomes secreted by vascular endothelial cells in the development of OA. Through in vivo and in vitro experiments, we demonstrated that exosomes derived from vascular endothelial cells decreased the ability of chondrocytes to resist oxidative stress by inhibiting autophagy and p21 expression, thereby increasing the cellular ROS content and inducing apoptosis. These findings indicate that exosomes derived from vascular endothelial cells promote the progression of OA, thus, providing new ideas for the diagnosis and treatment of OA.

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“…In recent years, the advantages of various new materials in cancer prevention and treatment have gradually emerged. Previous studies demonstrated that manganese-doped silica nanoparticle (MnMSN) can deplete GSH, and on-demand drug release can be achieved by loading sorafenib into MnMSN, while dual induction of ferroptosis is achieved by depletion of GSH and inhibition of intracellular GSH synthesis, showing efficient anti-HCC activity ( 17 ). Jiang and colleagues observed that a platelet membrane-camouflaged magnetic nanoparticle could sensitize ferroptosis by inhibiting system Xc − , which lead to immunosuppressive M2 TAM reversely polarize to the anti-tumor M1 phenotype, further increasing response to immunotherapy ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

The Identification and Validation of Two Heterogenous Subtypes and a Risk Signature Based on Ferroptosis in Hepatocellular Carcinoma

Wang

Liu

et al. 2021

Front. Oncol.

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BackgroundFerroptosis is essential for tumorigenesis and progression of hepatocellular carcinoma (HCC). The heterogeneity of ferroptosis and its relationship with tumor microenvironment (TME) have still remain elusive.MethodsBased on 74 ferroptosis related genes (FRGs) and 3,933 HCC samples from 32 datasets, we comprehensively explored the heterogenous ferroptosis subtypes. The clinical significance, functional status, immune infiltration, immune escape mechanisms, and genomic alterations of different subtypes were further investigated.ResultsWe identified and validated two heterogeneous ferroptosis subtypes: C1 was metabolismlowimmunityhigh subtype and C2 was metabolismhighimmunitylow subtype. Compared to C2, C1 owned worse prognosis, and C1 tended to occur in the patients with clinical characteristics such as younger, female, advanced stage, higher grade, vascular invasion. C1 and C2 were more sensitive to immunotherapy and sorafenib, respectively. The immune escape mechanisms of C1 might be accumulating more immunosuppressive cells, inhibitory cytokines, and immune checkpoints, while C2 was mainly associated with inferior immunogenicity, defecting in antigen presentation, and lacking leukocytes. In addition, C1 was characterized by BAP1 mutation, MYC amplification, and SCD1 methylation, while C2 was characterized by the significant alterations in cell cycle and chromatin remodeling processes. We also constructed and validated a robust and promising signature termed ferroptosis related risk score (FRRS) for assessing prognosis and immunotherapy.ConclusionWe identified and validated two heterogeneous ferroptosis subtypes and a reliable risk signature which used to assess prognosis and immunotherapy. Our results facilitated the understood of ferroptosis as well as clinical management and precise therapy of HCC.

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Targeted Manganese doped silica nano GSH-cleaner for treatment of Liver Cancer by destroying the intracellular redox homeostasis

Cited by 103 publications

References 48 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

Vascular endothelial cell-secreted exosomes facilitate osteoarthritis pathogenesis by promoting chondrocyte apoptosis

The Identification and Validation of Two Heterogenous Subtypes and a Risk Signature Based on Ferroptosis in Hepatocellular Carcinoma

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