|
1
|
Bai X, Duan T, Shao J, Zhang Y, Xing G, Wang J, Liu X, Wang M, He Y, Wang H, Zhang ZY, Ni M, Zhou JY, Pan J. CBX3 promotes multidrug resistance by suppressing ferroptosis in colorectal carcinoma via the CUL3/NRF2/GPX2 axis. Oncogene 2025; 44:1678-1693. [PMID: 40089640 PMCID: PMC12122363 DOI: 10.1038/s41388-025-03337-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 02/01/2025] [Accepted: 02/28/2025] [Indexed: 03/17/2025]
Abstract
Chemoresistance poses a significant challenge in colorectal cancer (CRC) treatment. However, the mechanisms underlying chemoresistance remain unclear. CBX3 promoted proliferation and metastasis in CRC. However, the role and mechanism of CBX3 in chemoresistance remain unknown. Therefore, we aimed to investigate the effects and mechanisms of CBX3 on multidrug resistance in CRC. Our studies showed that higher levels of CBX3 expression were associated with poor survival, especially in groups with progression following chemotherapy. CBX3 overexpression increased Irinotecan and Oxaliplatin resistance, whereas CBX3 knockdown suppressed multidrug resistance in CRC cells. Additionally, CBX3 inhibited ferroptosis associated with multidrug resistance, and the ferroptosis activators prevented CBX3 overexpression-mediated cell survival. RNA sequencing revealed that the NRF2-signaling pathway was involved in this process. CBX3-upregulated NRF2 protein expression by directly binding to the promoter of Cullin3 (CUL3) to suppress CUL3 transcription and CUL3-mediated NRF2 degradation. Moreover, Glutathione Peroxidase 2 (GPX2) was downstream of the CBX3-NRF2 pathway in CRC chemoresistance. ML385, an NRF2 inhibitor, suppressed GPX2 expression, and increased ferroptosis in PDX models. Our study identified CBX3/NRF2/GPX2 axis may be a novel signaling pathway that mediates multidrug resistance in CRC. This study proposes developing novel strategies for cancer treatment to overcome drug resistance in the future.
Collapse
Affiliation(s)
- Xiaoming Bai
- Department of Pathology, Nanjing Medical University, Nanjing, PR China
| | - Tinghong Duan
- Department of Pathology, Nanjing Medical University, Nanjing, PR China
- Department of Pathology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, PR China
| | - Jiaofang Shao
- Department of Bioinformatics, Nanjing Medical University, Nanjing, PR China
| | - Yutong Zhang
- Department of Pathology, Nanjing Medical University, Nanjing, PR China
| | - Guangyuan Xing
- Department of Pathology, Nanjing Medical University, Nanjing, PR China
| | - Jie Wang
- Department of Pathology, Nanjing Medical University, Nanjing, PR China
| | - Xue Liu
- Department of Pathology, Nanjing Medical University, Nanjing, PR China
| | - Min Wang
- Department of Pathology, Nanjing Medical University, Nanjing, PR China
| | - Yuanqiao He
- Center of Laboratory Animal Science, Nanchang University, Nanchang, PR China
- Key Laboratory of New Drug Evaluation and Transformation of Jiangxi Province, Nanchang Royo Biotech Co., Ltd, Nanchang, PR China
| | - Hai Wang
- Department of Pathology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, PR China
| | - Zhi-Yuan Zhang
- Department of Pathology, Nanjing Medical University, Nanjing, PR China
| | - Min Ni
- Department of Colorectum, Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine, Nanjing, PR China.
| | - Jin-Yong Zhou
- Jiangsu Province Key Laboratory of Tumor Systems Biology and Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, PR China.
- Central Laboratory, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, PR China.
| | - Jinshun Pan
- Department of Biotherapy, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, PR China.
| |
Collapse
|
|
2
|
Cheng Y, Song T, Yao J, Wang Q, Meng C, Feng F. Study on the mechanism of hsa_circ_0074763 regulating the miR-3667-3P/ACSL4 axis in liver fibrosis. Sci Rep 2025; 15:10548. [PMID: 40148434 PMCID: PMC11950437 DOI: 10.1038/s41598-025-91393-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 02/20/2025] [Indexed: 03/29/2025] Open
Abstract
This study aimed to investigate the involvement of hsa_circ_0074763 in the activation of HSCs (hepatic stellate cells ) and liver fibrosis. Additionally, it aimed to conduct a preliminary analysis of the molecular mechanism targeting miR-3667-3p/ACSL4 (Long-chain acyl-CoA synthetase 4), thereby providing novel molecular targets for liver fibrosis. The GEO database was utilized to identify differentially expressed hsa_circ_0074763 and determined its subcellular localization in LX-2 cells using fluorescence in situ hybridization. Bioinformatics analysis was employed for result prediction, and the interaction between hsa_circ_0074763 and miR-3667-3P was confirmed using dual-luciferase reporter gene assay. ACSL4 mediated ferroptosis was detected with kit. Hsa_circ_0074763 exhibits high expression levels in the fibrosis model. Validation through dual-luciferase reporter gene assays confirms the interaction between hsa_circ_0074763 and miR-3667-3P. Functional cell experiments demonstrate that overexpression of hsa_circ_0074763 promotes proliferation of LX-2 cells, elevates inflammation levels, and inhibits apoptosis. Additionally, ACSL4 has been identified as a direct target of miR-3667-3P, with overexpression of hsa_circ_0074763 counteracting the inhibitory effect on ACSL4 by suppressing miR-3667-3P. Overexpression of ACSL4 increased the expression levels of ROS (Lipid Oxidation), Iron (Ferro Orange) and MDA (Malondialdehyde), and decreased the expression levels of GPX4 (Glutathione peroxidase 4) and GSH (Glutathione). Our finding suggests that overexpression of hsa_circ_0074763 likely enhances the HSC activation through modulation of the miR-3667-3P/ACSL4 axis. Therefore, hsa_circ_0074763 holds potential as a therapeutic target for liver fibrosis.
Collapse
Affiliation(s)
- Yanling Cheng
- School of Public Health, North China University of Science and Technology, Tangshan, 063210, China
| | - Tiantian Song
- School of Public Health, North China University of Science and Technology, Tangshan, 063210, China
| | - Jiachen Yao
- School of Public Health, North China University of Science and Technology, Tangshan, 063210, China
| | - Qirong Wang
- School of Public Health, North China University of Science and Technology, Tangshan, 063210, China
| | - Chunyan Meng
- School of Public Health, North China University of Science and Technology, Tangshan, 063210, China.
| | - Fumin Feng
- School of Public Health, North China University of Science and Technology, Tangshan, 063210, China.
- Hebei Key Laboratory of Occupational Health and Safety for Coal Industry, Tangshan, China.
- Hebei Coordinated Innovation Center of Occupational Health and Safety, Tangshan, China.
| |
Collapse
|
|
3
|
Wu W, Ke W, Shi W, Lin T, Lin S, Lin M, Ma H, Gao H. PR/SET domain 1 targeting glutathione peroxidase 4 regulates chronic hepatitis B liver fibrosis through ferroptosis. Cytojournal 2024; 21:78. [PMID: 39917009 PMCID: PMC11801650 DOI: 10.25259/cytojournal_123_2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 11/28/2024] [Indexed: 02/09/2025] Open
Abstract
Objective Addressing the inhibition and reversal of chronic hepatitis B fibrosis is an urgent global challenge, which highlights the critical need to understand its underlying mechanisms. Inhibiting the activation of hepatic stellate cells (HSCs) is an important strategy for fibrosis reversal. In particular, the induction of ferroptosis in HSCs presents a promising avenue for curtailing liver fibrosis. Therefore, this study explores the influence of PR/SET domain 1 (PRDM1), which is a transcriptional regulator, on the progression of liver fibrosis by regulating HSC ferroptosis through glutathione peroxidase 4 (GPX4). Material and Methods We used protein-protein interaction databases to analyze the interacting proteins of GPX4. The messenger ribonucleic acid levels of PRDM1 and GPX4 in liver tissues with varying degrees of fibrosis were examined using quantitative polymerase chain reaction. Cell lines with interference and overexpression of PRDM1/GPX4 were established. Reactive oxygen species (ROS) activity, malondialdehyde (MDA) concentration, cell proliferation capacity, as well as the expression levels of GPX4, a-smooth muscle actin, vimentin, and desmin, were assessed to investigate the relationship between PRDM1 and hepatic fibrosis, as well as its impact on ferroptosis in HSCs. Results A significant negative correlation was observed between the transcriptional regulator PRDM1 and GPX4. As the degree of fibrosis worsened, PRDM1 decreased significantly, whereas GPX4 increased significantly. The overexpression of PRDM1 markedly increased ROS and MDA concentrations, but it decreased cell proliferation capacity, GPX4 expression levels, and activation marker protein levels. Interference with PRDM1 yielded opposite results. The expression level of GPX4 did not affect PRMD1 expression levels. Compared with cells with single interference of PRDM1, simultaneous interference with PRDM1 and GPX4 significantly inhibited the activity and proliferation capacity of HSCs. It also elevated ROS activity and MDA concentrations. When ferroptosis inhibitors were added, ROS activity and MDA concentrations decreased, and the proliferation capacity and activity of HSCs increased. Opposite results were obtained when PRDM1 and GPX4 were overexpressed simultaneously. Conclusion PRDM1 is implicated in the occurrence and progression of hepatic fibrosis. It may act as an upstream regulatory factor of GPX4, which exerts control over ferroptosis by suppressing the transcription of GPX4. Ultimately, the activation of HSCs is promoted.
Collapse
Affiliation(s)
- Wenjun Wu
- Department of Infectious Diseases, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Wenhai Ke
- Department of Infectious Diseases, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
- Pingtan Branch of Fujian Medical University Union Hospital, Fuzhou, China
| | - Weiping Shi
- Department of Biomedical Science, College of Biological Science and Engineering, Fuzhou University, Fuzhou, China
| | - Ting Lin
- Department of Infectious Diseases, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Shenglong Lin
- Department of Infectious Diseases, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Minghua Lin
- Department of Infectious Diseases, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Huaxi Ma
- Department of Infectious Diseases, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| | - Haibing Gao
- Department of Infectious Diseases, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China
| |
Collapse
|
|
4
|
Liu W, He Y, Chen K, Ye J, Yu L, Zhou C, Zhai W. YTHDF2 influences hepatic fibrosis by regulating ferroptosis in hepatic stellate cells by mediating the expression of ACSL4 in an m 6A-dependent manner. Acta Biochim Biophys Sin (Shanghai) 2024; 57:521-528. [PMID: 39716886 PMCID: PMC12040596 DOI: 10.3724/abbs.2024162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 06/18/2024] [Indexed: 12/25/2024] Open
Abstract
Hepatic fibrosis (HF) is an abnormal reparative response of the liver to chronic injury and is histologically reversible. In recent years, increasing interest has been given to changes in m 6A in liver disease. In this study, we explore the role of the m 6A-modified reading protein YTHDF2 in HF and its regulatory mechanism. The HF mouse model is generated through CCl 4 injection, and the cell model is via TGF-β stimulation. The liver tissues are subjected to hematoxylin-eosin, Masson, and α-SMA immunohistochemical staining. Reactive oxygen species (ROS) and iron levels are examined via relevant kits. Quantitative real-time PCR, immunofluorescence staining, and western blot analysis were conducted to measure the YTHDF2 and ACSL4 levels. RNA immunoprecipitation, methylated RNA immunoprecipitation, RNA pull-down, and polysome fractionation were performed to understand the regulatory mechanism by which YTHDF2 affects ACSL4. The results show that YTHDF2 is highly expressed after HF induction, and the inhibition of YTHDF2 reduces fibrosis as well as ROS and iron levels. In vitro, overexpression of YTHDF2 increases hepatic stellate cell activation, as well as ROS and iron levels, and this effect is blocked by the silencing of ACSL4. YTHDF2 acts as a regulator of ACSL4 expression and is involved in m 6A modification. In addition, in vivo experiments indicate that overexpression of ACSL4 reverses the attenuating effect of YTHDF2 interference on HFs. Therefore, YTHDF2 mediates the expression of the ferroptosis marker protein ACSL4 in an m 6A-dependent manner, thereby affecting HF.
Collapse
Affiliation(s)
- Wentao Liu
- />Department of Hepatobiliary and Pancreatic Surgerythe First Affiliated Hospital of Zhengzhou UniversityZhengzhou450000China
| | - Yuan He
- />Department of Hepatobiliary and Pancreatic Surgerythe First Affiliated Hospital of Zhengzhou UniversityZhengzhou450000China
| | - Kunlun Chen
- />Department of Hepatobiliary and Pancreatic Surgerythe First Affiliated Hospital of Zhengzhou UniversityZhengzhou450000China
| | - Jianwen Ye
- />Department of Hepatobiliary and Pancreatic Surgerythe First Affiliated Hospital of Zhengzhou UniversityZhengzhou450000China
| | - Long Yu
- />Department of Hepatobiliary and Pancreatic Surgerythe First Affiliated Hospital of Zhengzhou UniversityZhengzhou450000China
| | - Chuang Zhou
- />Department of Hepatobiliary and Pancreatic Surgerythe First Affiliated Hospital of Zhengzhou UniversityZhengzhou450000China
| | - Wenlong Zhai
- />Department of Hepatobiliary and Pancreatic Surgerythe First Affiliated Hospital of Zhengzhou UniversityZhengzhou450000China
| |
Collapse
|
|
5
|
Zhang M, Xu L, Zhu C, Zhang Y, Luo R, Ren J, Yu J, Zhang Y, Liang G, Zhang Y. Magnoflorine ameliorates hepatic fibrosis and hepatic stellate cell activation by regulating ferroptosis signaling pathway. Heliyon 2024; 10:e39892. [PMID: 39634391 PMCID: PMC11615489 DOI: 10.1016/j.heliyon.2024.e39892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 10/25/2024] [Accepted: 10/25/2024] [Indexed: 12/07/2024] Open
Abstract
Liver fibrosis is a chronic liver disease that brings a heavy economic burden to the world and has attracted global attention. Although the pathological mechanisms and treatment strategies of liver fibrosis have been extensively studied, there are currently no effective targeted drugs for the prevention and treatment of liver fibrosis in clinical practice. Therefore, it is imperative to seek and develop effective treatment strategies and drugs for liver fibrosis. Magnoflorine (MAG) is a natural product with multiple pharmacological activities. Thus, in this study, we will explore the effect of MAG on alleviating liver fibrosis in mice and its mechanism of action. Our study indicates that MAG can alleviate liver damage, improve liver collagen deposition, and significantly reduced the expression levels of hepatic stellate cells (HSCs) activation markers in vivo. Additionally, the findings of this study indicate that MAG can inhibit the transforming growth factor-beta (TGF-β)/Smad signaling pathway. Bioinformatics analysis suggests that the alleviating effect of MAG on liver fibrosis may be associated with ferroptosis. Interestingly, in vitro experiments have demonstrated that MAG slows down the progression of liver fibrosis by inhibiting the activation of HSCs, and further confirms that MAG promotes ferroptosis in ROS-mediated activated HSCs. In short, MAG has a good alleviating effect on liver fibrosis and will be a potential candidate drug for the treatment of liver fibrosis.
Collapse
Affiliation(s)
- Meiling Zhang
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China
| | - Lenan Xu
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China
| | - Chengkai Zhu
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China
| | - Yawen Zhang
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China
| | - Ruixiang Luo
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China
| | - Juan Ren
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China
| | - Jie Yu
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China
| | - Yanmei Zhang
- School of Laboratory Medicine and Bioengineering, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China
| | - Guang Liang
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Yi Zhang
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 310012, China
| |
Collapse
|
|
6
|
Shou BB, Li TT, Hu XJ, Liu GH, Ren HT, Lin JH, Xie J, Liu LY, Lou CW. Crafting and analyzing nonwovens enhanced with antimicrobial metal particles and diverse mechanisms via substitution reaction. MATERIALS TODAY CHEMISTRY 2024; 40:102260. [DOI: 10.1016/j.mtchem.2024.102260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
7
|
Cao X, Chen Y, Chen Y, Jiang M. The Role of Tripartite Motif Family Proteins in Chronic Liver Diseases: Molecular Mechanisms and Therapeutic Potential. Biomolecules 2024; 14:1038. [PMID: 39199424 PMCID: PMC11352684 DOI: 10.3390/biom14081038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 08/20/2024] [Accepted: 08/20/2024] [Indexed: 09/01/2024] Open
Abstract
The worldwide impact of liver diseases is increasing steadily, with a consistent upswing evidenced in incidence and mortality rates. Chronic liver diseases (CLDs) refer to the liver function's progressive deterioration exceeding six months, which includes abnormal clotting factors, detoxification failure, and hepatic cholestasis. The most common etiologies of CLDs are mainly composed of chronic viral hepatitis, MAFLD/MASH, alcoholic liver disease, and genetic factors, which induce inflammation and harm to the liver, ultimately resulting in cirrhosis, the irreversible final stage of CLDs. The latest research has shown that tripartite motif family proteins (TRIMs) function as E3 ligases, which participate in the progression of CLDs by regulating gene and protein expression levels through post-translational modification. In this review, our objective is to clarify the molecular mechanisms and potential therapeutic targets of TRIMs in CLDs and provide insights for therapy guidelines and future research.
Collapse
Affiliation(s)
- Xiwen Cao
- The Queen Mary School, Jiangxi Medical College, Nanchang University, 999 Xuefu Road, Nanchang 330031, China;
| | - Yinni Chen
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, 999 Xuefu Road, Nanchang 330031, China;
| | - Yuanli Chen
- Key Laboratory of Major Metabolic Diseases, Nutritional Regulation of Anhui Department of Education, College of Food and Biological Engineering, Hefei University of Technology, Hefei 230002, China;
| | - Meixiu Jiang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, 999 Xuefu Road, Nanchang 330031, China;
| |
Collapse
|
|
8
|
Faria RL, Prado FM, Junqueira HC, Fabiano KC, Diniz LR, Baptista MS, Di Mascio P, Miyamoto S. Plasmalogen oxidation induces the generation of excited molecules and electrophilic lipid species. PNAS NEXUS 2024; 3:pgae216. [PMID: 38894877 PMCID: PMC11184980 DOI: 10.1093/pnasnexus/pgae216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 05/24/2024] [Indexed: 06/21/2024]
Abstract
Plasmalogens are glycerophospholipids with a vinyl ether linkage at the sn-1 position of the glycerol backbone. Despite being suggested as antioxidants due to the high reactivity of their vinyl ether groups with reactive oxygen species, our study reveals the generation of subsequent reactive oxygen and electrophilic lipid species from oxidized plasmalogen intermediates. By conducting a comprehensive analysis of the oxidation products by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS), we demonstrate that singlet molecular oxygen [O2 (1Δg)] reacts with the vinyl ether bond, producing hydroperoxyacetal as a major primary product (97%) together with minor quantities of dioxetane (3%). Furthermore, we show that these primary oxidized intermediates are capable of further generating reactive species including excited triplet carbonyls and O2 (1Δg) as well as electrophilic phospholipid and fatty aldehyde species as secondary reaction products. The generation of excited triplet carbonyls from dioxetane thermal decomposition was confirmed by light emission measurements in the visible region using dibromoanthracene as a triplet enhancer. Moreover, O2 (1Δg) generation from dioxetane and hydroperoxyacetal was evidenced by detection of near-infrared light emission at 1,270 nm and chemical trapping experiments. Additionally, we have thoroughly characterized alpha-beta unsaturated phospholipid and fatty aldehydes by LC-HRMS analysis using two probes that specifically react with aldehydes and alpha-beta unsaturated carbonyls. Overall, our findings demonstrate the generation of excited molecules and electrophilic lipid species from oxidized plasmalogen species unveiling the potential prooxidant nature of plasmalogen-oxidized products.
Collapse
Affiliation(s)
- Rodrigo L Faria
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, São Paulo, SP 05508-000, Brazil
| | - Fernanda M Prado
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, São Paulo, SP 05508-000, Brazil
| | - Helena C Junqueira
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, São Paulo, SP 05508-000, Brazil
| | - Karen C Fabiano
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, São Paulo, SP 05508-000, Brazil
| | - Larissa R Diniz
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, São Paulo, SP 05508-000, Brazil
| | - Mauricio S Baptista
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, São Paulo, SP 05508-000, Brazil
| | - Paolo Di Mascio
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, São Paulo, SP 05508-000, Brazil
| | - Sayuri Miyamoto
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, São Paulo, SP 05508-000, Brazil
| |
Collapse
|
|
9
|
Vermonden P, Martin M, Glowacka K, Neefs I, Ecker J, Höring M, Liebisch G, Debier C, Feron O, Larondelle Y. Phospholipase PLA2G7 is complementary to GPX4 in mitigating punicic-acid-induced ferroptosis in prostate cancer cells. iScience 2024; 27:109774. [PMID: 38711443 PMCID: PMC11070704 DOI: 10.1016/j.isci.2024.109774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 03/08/2024] [Accepted: 04/15/2024] [Indexed: 05/08/2024] Open
Abstract
Ferroptosis is a cell death pathway that can be promoted by peroxidizable polyunsaturated fatty acids in cancer cells. Here, we investigated the mechanisms underlying the toxicity of punicic acid (PunA), an isomer of conjugated linolenic acids (CLnAs) bearing three conjugated double bonds highly prone to peroxidation, on prostate cancer (PCa) cells. PunA induced ferroptosis in PCa cells and triggered massive lipidome remodeling, more strongly in PC3 androgen-negative cells than in androgen-positive cells. The greater sensitivity of androgen-negative cells to PunA was associated with lower expression of glutathione peroxidase 4 (GPX4). We then identified the phospholipase PLA2G7 as a PunA-induced ferroptosis suppressor in PCa cells. Overexpressing PLA2G7 decreased lipid peroxidation levels, suggesting that PLA2G7 hydrolyzes hydroperoxide-containing phospholipids, thus preventing ferroptosis. Importantly, overexpressing both PLA2G7 and GPX4 strongly prevented PunA-induced ferroptosis in androgen-negative PCa cells. This study shows that PLA2G7 acts complementary to GPX4 to protect PCa cells from CLnA-induced ferroptosis.
Collapse
Affiliation(s)
- Perrine Vermonden
- Louvain Institute of Biomolecular Science and Technology, UCLouvain, 1348 Louvain-la-Neuve, Belgium
| | - Manon Martin
- Louvain Institute of Biomolecular Science and Technology, UCLouvain, 1348 Louvain-la-Neuve, Belgium
| | - Katarzyna Glowacka
- FATH, Institut de recherche Expérimentale et Clinique, UCLouvain, 1200 Woluwe Saint-Lambert, Belgium
| | - Ineke Neefs
- Louvain Institute of Biomolecular Science and Technology, UCLouvain, 1348 Louvain-la-Neuve, Belgium
| | - Josef Ecker
- Functional Lipidomics and Metabolism Research, Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany
| | - Marcus Höring
- Lipidomics Lab, Institute of Clinical Chemistry and Laboratory Medicine, University Hospital of Regensburg, Regensburg, Germany
| | - Gerhard Liebisch
- Lipidomics Lab, Institute of Clinical Chemistry and Laboratory Medicine, University Hospital of Regensburg, Regensburg, Germany
| | - Cathy Debier
- Louvain Institute of Biomolecular Science and Technology, UCLouvain, 1348 Louvain-la-Neuve, Belgium
| | - Olivier Feron
- FATH, Institut de recherche Expérimentale et Clinique, UCLouvain, 1200 Woluwe Saint-Lambert, Belgium
| | - Yvan Larondelle
- Louvain Institute of Biomolecular Science and Technology, UCLouvain, 1348 Louvain-la-Neuve, Belgium
| |
Collapse
|
|
10
|
Horvat N, Chocarro S, Marques O, Bauer TA, Qiu R, Diaz-Jimenez A, Helm B, Chen Y, Sawall S, Sparla R, Su L, Klingmüller U, Barz M, Hentze MW, Sotillo R, Muckenthaler MU. Superparamagnetic Iron Oxide Nanoparticles Reprogram the Tumor Microenvironment and Reduce Lung Cancer Regrowth after Crizotinib Treatment. ACS NANO 2024; 18:11025-11041. [PMID: 38626916 PMCID: PMC11064219 DOI: 10.1021/acsnano.3c08335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 03/11/2024] [Accepted: 03/15/2024] [Indexed: 05/01/2024]
Abstract
ALK-positive NSCLC patients demonstrate initial responses to ALK tyrosine kinase inhibitor (TKI) treatments, but eventually develop resistance, causing rapid tumor relapse and poor survival rates. Growing evidence suggests that the combination of drug and immune therapies greatly improves patient survival; however, due to the low immunogenicity of the tumors, ALK-positive patients do not respond to currently available immunotherapies. Tumor-associated macrophages (TAMs) play a crucial role in facilitating lung cancer growth by suppressing tumoricidal immune activation and absorbing chemotherapeutics. However, they can also be programmed toward a pro-inflammatory tumor suppressive phenotype, which represents a highly active area of therapy development. Iron loading of TAMs can achieve such reprogramming correlating with an improved prognosis in lung cancer patients. We previously showed that superparamagnetic iron oxide nanoparticles containing core-cross-linked polymer micelles (SPION-CCPMs) target macrophages and stimulate pro-inflammatory activation. Here, we show that SPION-CCPMs stimulate TAMs to secrete reactive nitrogen species and cytokines that exert tumoricidal activity. We further show that SPION-CCPMs reshape the immunosuppressive Eml4-Alk lung tumor microenvironment (TME) toward a cytotoxic profile hallmarked by the recruitment of CD8+ T cells, suggesting a multifactorial benefit of SPION-CCPM application. When intratracheally instilled into lung cancer-bearing mice, SPION-CCPMs delay tumor growth and, after first line therapy with a TKI, halt the regrowth of relapsing tumors. These findings identify SPIONs-CCPMs as an adjuvant therapy, which remodels the TME, resulting in a delay in the appearance of resistant tumors.
Collapse
Affiliation(s)
- Natalie
K. Horvat
- Department
of Pediatric Hematology, Oncology, Immunology and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany
- Molecular
Medicine Partnership Unit (MMPU), Otto-Meyerhof-Zentrum, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany
- Ruprecht
Karl University of Heidelberg, 69120, Heidelberg, Germany
| | - Sara Chocarro
- Division
of Molecular Thoracic Oncology, German Cancer
Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
- Ruprecht
Karl University of Heidelberg, 69120, Heidelberg, Germany
| | - Oriana Marques
- Department
of Pediatric Hematology, Oncology, Immunology and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany
- Molecular
Medicine Partnership Unit (MMPU), Otto-Meyerhof-Zentrum, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany
| | - Tobias A. Bauer
- Leiden
Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, 2333CC, Leiden, The Netherlands
| | - Ruiyue Qiu
- Department
of Pediatric Hematology, Oncology, Immunology and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany
| | - Alberto Diaz-Jimenez
- Division
of Molecular Thoracic Oncology, German Cancer
Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
- Ruprecht
Karl University of Heidelberg, 69120, Heidelberg, Germany
| | - Barbara Helm
- Division
of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
- German
Center for Lung Research (DZL) and Translational Lung Research Center
Heidelberg (TRLC), 69120, Heidelberg, Germany
| | - Yuanyuan Chen
- Division
of Molecular Thoracic Oncology, German Cancer
Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Stefan Sawall
- X-ray
Imaging and CT, German Cancer Research Center
(DKFZ), Im Neuenheimer
Feld 280, 69120, Heidelberg, Germany
| | - Richard Sparla
- Department
of Pediatric Hematology, Oncology, Immunology and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany
| | - Lu Su
- Leiden
Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, 2333CC, Leiden, The Netherlands
| | - Ursula Klingmüller
- Division
of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
- German
Center for Lung Research (DZL) and Translational Lung Research Center
Heidelberg (TRLC), 69120, Heidelberg, Germany
- German
Consortium for Translational Cancer Research (DKTK), 69120, Heidelberg, Germany
| | - Matthias Barz
- Leiden
Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, 2333CC, Leiden, The Netherlands
- Department
of Dermatology, University Medical Center
of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Matthias W. Hentze
- Molecular
Medicine Partnership Unit (MMPU), Otto-Meyerhof-Zentrum, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany
- European Molecular Biology Laboratory (EMBL), Meyerhofstr.1, 69117, Heidelberg, Germany
| | - Rocío Sotillo
- Division
of Molecular Thoracic Oncology, German Cancer
Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
- German
Center for Lung Research (DZL) and Translational Lung Research Center
Heidelberg (TRLC), 69120, Heidelberg, Germany
- German
Consortium for Translational Cancer Research (DKTK), 69120, Heidelberg, Germany
| | - Martina U. Muckenthaler
- Department
of Pediatric Hematology, Oncology, Immunology and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany
- Molecular
Medicine Partnership Unit (MMPU), Otto-Meyerhof-Zentrum, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany
- German
Center for Lung Research (DZL) and Translational Lung Research Center
Heidelberg (TRLC), 69120, Heidelberg, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site, 69120, Heidelberg/Mannheim, Germany
| |
Collapse
|
|
11
|
Yu T, Lu X, Liang Y, Yang L, Yin Y, Chen H. Naringenin alleviates liver fibrosis by triggering autophagy-dependent ferroptosis in hepatic stellate cells. Heliyon 2024; 10:e28865. [PMID: 38576562 PMCID: PMC10990976 DOI: 10.1016/j.heliyon.2024.e28865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 03/26/2024] [Accepted: 03/26/2024] [Indexed: 04/06/2024] Open
Abstract
Inhibition of activated hepatic stellate cells (HSCs) is a promising approach for treating liver fibrosis, and the ferroptosis has emerged as a pivotal mechanism to achieve this inhibition. The effects of naringenin, a flavonoid with anti-inflammatory properties, have not been thoroughly examined in liver fibrosis. Therefore, we used cholestasis model to study the effect of naringenin on liver fibrosis. Our findings demonstrated a significant exacerbation of liver tissue damage and fibrosis in mice subjected to bile duct ligation (BDL), accompanied by a substantial upregulation of fibrogenesis-related gene expression. Notably, naringenin administration markedly alleviated liver injury and fibrosis in these mice. Furthermore, naringenin exhibited inhibitory effects on the activation of HSCs, concurrently inducing ferroptosis. Importantly, naringenin significantly increased autophagic activity in HSCs. This effect was counteracted by co-administration of the autophagy inhibitor 3-MA, leading to a notable reduction in naringenin-induced HSC ferroptosis. In BDL model mice, naringenin demonstrated a mitigating effect on liver fibrosis, suggesting a potential correlation with naringenin-induced ferroptosis of HSCs. These results provide novel insights into the molecular mechanisms of naringenin-induced ferroptosis and highlight autophagy-dependent ferroptosis as a promising therapeutic strategy for liver fibrosis.
Collapse
Affiliation(s)
- Ting Yu
- Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, People's Republic of China
| | - Xuejia Lu
- Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, People's Republic of China
| | - Yan Liang
- Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, People's Republic of China
| | - Lin Yang
- Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, People's Republic of China
| | - Yuehan Yin
- China HuaYou Group Corporation, Beijing, 100724, People's Republic of China
| | - Hong Chen
- Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao, Nanjing, Jiangsu, 210009, People's Republic of China
| |
Collapse
|
|
12
|
Wang J, Zhang H, Chen L, Fu K, Yan Y, Liu Z. CircDCBLD2 alleviates liver fibrosis by regulating ferroptosis via facilitating STUB1-mediated PARK7 ubiquitination degradation. J Gastroenterol 2024; 59:229-249. [PMID: 38310161 DOI: 10.1007/s00535-023-02068-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Accepted: 12/13/2023] [Indexed: 02/05/2024]
Abstract
BACKGROUND Liver fibrosis can progress to cirrhosis and hepatic carcinoma without treatment. CircDCBLD2 was found to be downregulated in liver fibrosis. However, the precise underlying mechanism requires further investigation. METHODS qRT-PCR, Western blot, and immunohistochemistry assays were used to detect the related molecule levels. HE, Masson's trichrome, and Sirius Red staining were used to assess the pathological changes in mice's liver tissues. Flow cytometric analysis and commercial kit were used to assess the levels of lipid reactive oxygen species (ROS), malonaldehyde (MDA), glutathione (GSH), and iron. Cell viability was assessed by MTT. Immunoprecipitation was used to study the ubiquitination of PARK7. Mitophagy was determined by immunostaining and confocal imaging. RIP and Co-IP assays were used to assess the interactions of circDCBLD2/HuR, HuR/STUB1, and STUB1/PARK7. Fluorescence in situ hybridization and immunofluorescence staining were used to assess the co-localization of circDCBLD2 and HuR. RESULTS CircDCBLD2 was downregulated, whereas PARK7 was upregulated in liver fibrosis. Ferroptosis activators increased circDCBLD2 while decreasing PARK7 in hepatic stellate cells (HSCs) and mice with liver fibrosis. CircDCBLD2 overexpression reduced cell viability and GSH, PARK7, and GPX4 expression in erastin-treated HSCs while increasing MDA and iron levels, whereas circDCBLD2 knockdown had the opposite effect. CircDCBLD2 overexpression increased STUB1-mediated PARK7 ubiquitination by promoting HuR-STUB1 binding and thus increasing STUB1 mRNA stability. PARK7 overexpression or HuR knockdown reversed the effects of circDCBLD2 overexpression on HSC activation and ferroptosis. CircDCBLD2 reduced liver fibrosis in mice by inhibiting PARK7. CONCLUSION CircDCBLD2 overexpression increased PARK7 ubiquitination degradation by upregulating STUB1 through its interaction with HuR, inhibiting HSC activation and promoting HSC ferroptosis, ultimately enhancing liver fibrosis.
Collapse
Affiliation(s)
- Juan Wang
- Department of Infectious Disease, Third Xiangya Hospital, Central South University, Hunan, 410013, China
| | - Haoye Zhang
- Department of Infectious Disease, Third Xiangya Hospital, Central South University, Hunan, 410013, China
| | - Limin Chen
- Department of Infectious Disease, Third Xiangya Hospital, Central South University, Hunan, 410013, China
| | - Kangkang Fu
- Department of Infectious Disease, Third Xiangya Hospital, Central South University, Hunan, 410013, China
| | - Yu Yan
- Department of Infectious Disease, Third Xiangya Hospital, Central South University, Hunan, 410013, China
| | - Zhenguo Liu
- Department of Infectious Disease, Third Xiangya Hospital, Central South University, Hunan, 410013, China.
- Changsha & Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Hunan, 410008, China.
| |
Collapse
|
|
13
|
Chen J, Zhang R, Li F, Lin S, Wang J. Integrated analysis and validation of TRIM23/p53 signaling pathway in hepatic stellate cells ferroptosis and liver fibrosis. Dig Liver Dis 2024; 56:281-290. [PMID: 37495427 DOI: 10.1016/j.dld.2023.07.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 06/08/2023] [Accepted: 07/11/2023] [Indexed: 07/28/2023]
Abstract
BACKGROUND Tripartite motif containing proteins 23(TRIM23) is identified as an E3 ubiquitin ligase involved in signal transduction, but its role in liver fibrosis remains unknown. AIMS To investigate the effects and mechanisms of TRIM23 on hepatic stellate cells(HSCs) ferroptosis and liver fibrosis. METHODS We utilized the Gene Expression Omibus database to identify differentially expressed genes and downstream pathways. TRIM23 expression was examined in fibrotic liver tissues. The effects of TRIM23 on HSCs ferroptosis were validated through assessing cell viability, lipid peroxidation, and ferroptotic markers using HSC-T6 cell lines and primary rat HSCs. Co-immunoprecipitation assays were conducted to analyze the interactions between TRIM23 and p53. A CCl4-induced liver fibrosis rat model was employed to confirm the in vivo effects. RESULTS TRIM23 expression was positively correlated with the severity of liver fibrosis. Upregulated TRIM23 expression promoted HSCs viability and activation by attenuating ferroptosis. Furthermore, the upregulation of TRIM23 expression significantly enhanced p53 ubiquitination. In contrast, TRIM23 knockdown induced HSCs ferroptosis by regulating p53, leading to the suppression of cell viability and activation. Silencing TRIM23 led to the regression of liver fibrosis induced by CCl4 treatment in vivo. CONCLUSION Our study uncovers a novel mechanism in which TRIM23 inhibits HSCs ferroptosis, promotes cell activation and contributes to liver fibrosis by regulating p53 ubiquitination.
Collapse
Affiliation(s)
- Jie Chen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, PR China; Shanghai Institute of Liver Disease, Shanghai, PR China; Evidence-Based Medicine Center, Fudan University, Shanghai, PR China
| | - Rui Zhang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, PR China; Shanghai Institute of Liver Disease, Shanghai, PR China
| | - Feng Li
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, PR China; Shanghai Institute of Liver Disease, Shanghai, PR China
| | - Shengli Lin
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China.
| | - Jian Wang
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, PR China; Shanghai Institute of Liver Disease, Shanghai, PR China.
| |
Collapse
|
|
14
|
Williams CH, Neitzel LR, Cornell J, Rea S, Mills I, Silver MS, Ahmad JD, Birukov KG, Birukova A, Brem H, Tyler B, Bar EE, Hong CC. GPR68-ATF4 signaling is a novel prosurvival pathway in glioblastoma activated by acidic extracellular microenvironment. Exp Hematol Oncol 2024; 13:13. [PMID: 38291540 PMCID: PMC10829393 DOI: 10.1186/s40164-023-00468-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 12/25/2023] [Indexed: 02/01/2024] Open
Abstract
BACKGROUND Glioblastoma multiforme (GBM) stands as a formidable challenge in oncology because of its aggressive nature and severely limited treatment options. Despite decades of research, the survival rates for GBM remain effectively stagnant. A defining hallmark of GBM is a highly acidic tumor microenvironment, which is thought to activate pro-tumorigenic pathways. This acidification is the result of altered tumor metabolism favoring aerobic glycolysis, a phenomenon known as the Warburg effect. Low extracellular pH confers radioresistant tumors to glial cells. Notably GPR68, an acid sensing GPCR, is upregulated in radioresistant GBM. Usage of Lorazepam, which has off target agonism of GPR68, is linked to worse clinical outcomes for a variety of cancers. However, the role of tumor microenvironment acidification in GPR68 activation has not been assessed in cancer. Here we interrogate the role of GPR68 specifically in GBM cells using a novel highly specific small molecule inhibitor of GPR68 named Ogremorphin (OGM) to induce the iron mediated cell death pathway: ferroptosis. METHOD OGM was identified in a non-biased zebrafish embryonic development screen and validated with Morpholino and CRISPR based approaches. Next, A GPI-anchored pH reporter, pHluorin2, was stably expressed in U87 glioblastoma cells to probe extracellular acidification. Cell survival assays, via nuclei counting and cell titer glo, were used to demonstrate sensitivity to GPR68 inhibition in twelve immortalized and PDX GBM lines. To determine GPR68 inhibition's mechanism of cell death we use DAVID pathway analysis of RNAseq. Our major indication, ferroptosis, was then confirmed by western blotting and qRT-PCR of reporter genes including TFRC. This finding was further validated by transmission electron microscopy and liperfluo staining to assess lipid peroxidation. Lastly, we use siRNA and CRISPRi to demonstrate the critical role of ATF4 suppression via GPR68 for GBM survival. RESULTS We used a pHLourin2 probe to demonstrate how glioblastoma cells acidify their microenvironment to activate the commonly over expressed acid sensing GPCR, GPR68. Using our small molecule inhibitor OGM and genetic means, we show that blocking GPR68 signaling results in robust cell death in all thirteen glioblastoma cell lines tested, irrespective of genetic and phenotypic heterogeneity, or resistance to the mainstay GBM chemotherapeutic temozolomide. We use U87 and U138 glioblastoma cell lines to show how selective induction of ferroptosis occurs in an ATF4-dependent manner. Importantly, OGM was not-acutely toxic to zebrafish and its inhibitory effects were found to spare non-malignant neural cells. CONCLUSION These results indicate GPR68 emerges as a critical sensor for an autocrine pro-tumorigenic signaling cascade triggered by extracellular acidification in glioblastoma cells. In this context, GPR68 suppresses ATF4, inhibition of GPR68 increases expression of ATF4 which leads to ferroptotic cell death. These findings provide a promising therapeutic approach to selectively induce ferroptosis in glioblastoma cells while sparing healthy neural tissue.
Collapse
Affiliation(s)
- Charles H Williams
- Department of Medicine, Michigan State University College of Human Medicine, East Lansing, MI, USA
- Henry Ford Health + Michigan State Health Sciences, Detroit, MI, USA
| | - Leif R Neitzel
- Department of Medicine, Michigan State University College of Human Medicine, East Lansing, MI, USA
- Henry Ford Health + Michigan State Health Sciences, Detroit, MI, USA
| | - Jessica Cornell
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Samantha Rea
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Ian Mills
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Maya S Silver
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Jovanni D Ahmad
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Konstantin G Birukov
- Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Anna Birukova
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Henry Brem
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Betty Tyler
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Eli E Bar
- Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA
- University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA
| | - Charles C Hong
- Department of Medicine, Michigan State University College of Human Medicine, East Lansing, MI, USA.
- Henry Ford Health + Michigan State Health Sciences, Detroit, MI, USA.
| |
Collapse
|
|
15
|
Zhang Y, Huang Z, Li K, Xie G, Feng Y, Wang Z, Li N, Liu R, Ding Y, Wang J, Yang J, Jia Z. TrkA promotes MDM2-mediated AGPS ubiquitination and degradation to trigger prostate cancer progression. J Exp Clin Cancer Res 2024; 43:16. [PMID: 38200609 PMCID: PMC10782585 DOI: 10.1186/s13046-023-02920-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 11/30/2023] [Indexed: 01/12/2024] Open
Abstract
BACKGROUND As a novel necrosis manner, ferroptosis has been increasingly reported to play a role in tumor progression and treatment, however, the specific mechanisms underlying its development in prostate cancer remain unclear. Growing evidence showed that peroxisome plays a key role in ferroptosis. Herein, we identified a novel mechanism for the involvement of ferroptosis in prostate cancer progression, which may provide a new strategy for clinical treatment of prostate cancer. METHODS Label-Free Mass spectrometry was used to screen and identify candidate proteins after ferroptosis inducer-ML210 treatment. Immunohistochemistry was undertaken to explore the protein expression of AGPS in prostate cancer tissues compared with normal tissues. Co-immunoprecipitation and GST pull-down were used to identify the directly binding of AGPS to MDM2 in vivo and in vitro. CCK8 assay and colony formation assay were used to illustrate the key role of AGPS in the progression of prostate cancer in vitro. The xenograft model was established to verify the key role of AGPS in the progression of prostate cancer in vivo. RESULTS AGPS protein expression was downregulated in prostate cancer tissues compared with normal tissues from the first affiliated hospital of Zhengzhou University dataset. Lower expression was correlated with poorer overall survival of patients compared to those with high expression of AGPS. In addition, AGPS can promote ferroptosis by modulating the function of peroxisome-resulting in the lower survival of prostate cancer cells. Furthermore, it was shown that AGPS can be ubiquitinated and degraded by the E3 ligase-MDM2 through the proteasomal pathway. Meanwhile, kinase TrkA can promote the combination of AGPS and MDM2 by phosphorylating AGPS at Y451 site. It was verified that kinase TrkA inhibitor-Larotrectinib can increase the susceptibility of prostate cancer cells to ferroptosis, which leads to the inhibition of prostate cancer proliferation to a great extent in vitro and in vivo. CONCLUSION Based on these findings, we proposed the combination of ferroptosis inducer and TrkA inhibitor to synergistically exert anti-tumor effects, which may provide a new strategy for the clinical treatment of prostate cancer.
Collapse
Affiliation(s)
- Yu Zhang
- Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, 55905, USA
- Academy of Medical Science, Zhengzhou University, Zhengzhou, 450052, China
| | - Zhenlin Huang
- Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Keqiang Li
- Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Academy of Medical Science, Zhengzhou University, Zhengzhou, 450052, China
| | - Guoqing Xie
- Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Academy of Medical Science, Zhengzhou University, Zhengzhou, 450052, China
| | - Yuankang Feng
- Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Zihao Wang
- Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Ningyang Li
- Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Ruoyang Liu
- Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yinghui Ding
- Department of Otorhinolaryngology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Jun Wang
- Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Jinjian Yang
- Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| | - Zhankui Jia
- Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
| |
Collapse
|
|
16
|
Bi Y, Liu S, Qin X, Abudureyimu M, Wang L, Zou R, Ajoolabady A, Zhang W, Peng H, Ren J, Zhang Y. FUNDC1 interacts with GPx4 to govern hepatic ferroptosis and fibrotic injury through a mitophagy-dependent manner. J Adv Res 2024; 55:45-60. [PMID: 36828120 PMCID: PMC10770120 DOI: 10.1016/j.jare.2023.02.012] [Citation(s) in RCA: 67] [Impact Index Per Article: 67.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 02/17/2023] [Accepted: 02/19/2023] [Indexed: 02/24/2023] Open
Abstract
INTRODUCTION Liver fibrosis is a life-threatening pathological anomaly which usually evolves into advanced liver cirrhosis and hepatocellular carcinoma although limited therapeutic option is readily available. FUN14 domain containing 1 (FUNDC1) is a mitophagy receptor with little information in liver fibrosis. OBJECTIVE This study was designed to examine the role for FUNDC1 in carbon tetrachloride (CCl4)-induced liver injury. METHODS GEO database analysis and subsequent validation of biological processes including western blot, immunofluorescence, and co-immunoprecipitation were applied to clarify the regulatory role of FUNDC1 on mitophagy and ferroptosis. RESULTS Our data revealed elevated FUNDC1 levels in liver tissues of patients with liver fibrotic injury and CCl4-challenged mice. FUNDC1 deletion protected against CCl4-induced hepatic anomalies in mice. Moreover, FUNDC1 deletion ameliorated CCl4-induced ferroptosis in vivo and in vitro. Mechanically, FUNDC1 interacted with glutathione peroxidase (GPx4), a selenoenzyme to neutralize lipid hydroperoxides and ferroptosis, via its 96-133 amino acid domain to facilitate GPx4 recruitment into mitochondria from cytoplasm. GPx4 entered mitochondria through mitochondrial protein import system-the translocase of outer membrane/translocase of inner membrane (TOM/TIM) complex, prior to degradation of GPx4 mainly through mitophagy along with ROS-induced damaged mitochondria, resulting in hepatocyte ferroptosis. CONCLUSION Taken together, our data favored that FUNDC1 promoted hepatocyte injury through GPx4 binding to facilitate its mitochondrial translocation through TOM/TIM complex, where GPx4 was degraded by mitophagy to trigger ferroptosis. Targeting FUNDC1 may be a promising therapeutic approach for liver fibrosis.
Collapse
Affiliation(s)
- Yaguang Bi
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Shuolin Liu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China
| | - Xing Qin
- Department of Cardiology, Xijing Hospital, Air Force Medical University, Xi'an 710032, China
| | - Miyesaier Abudureyimu
- Cardiovascular Department, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China
| | - Lu Wang
- Institute of Digestive Diseases, Xijing Hospital, Air Force Medical University, Xi'an 710032, China; State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Air Force Medical University, Xi'an 710032, China
| | - Rongjun Zou
- Department of Cardiovascular Surgery, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine,Guangzhou 510120, Guangdong, China; The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China
| | - Amir Ajoolabady
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China
| | - Wenjing Zhang
- Department of Emergency, Shanghai Tenth People's Hospital, School of Medicine Tongji University, Shanghai 200072, China
| | - Hu Peng
- Department of Emergency, Shanghai Tenth People's Hospital, School of Medicine Tongji University, Shanghai 200072, China
| | - Jun Ren
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.
| | - Yingmei Zhang
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China; National Clinical Research Center for Interventional Medicine, Shanghai 200032, China.
| |
Collapse
|
|
17
|
Chen J, Li T, Zhou N, He Y, Zhong J, Ma C, Zeng M, Ji J, Huang JD, Ke Y, Sun H. Engineered Salmonella inhibits GPX4 expression and induces ferroptosis to suppress glioma growth in vitro and in vivo. J Neurooncol 2023; 163:607-622. [PMID: 37351767 DOI: 10.1007/s11060-023-04369-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 06/08/2023] [Indexed: 06/24/2023]
Abstract
PURPOSE Glioma is a life-threatening malignancy where conventional therapies are ineffective. Bacterial cancer therapy has shown potential for glioma treatment, in particular, the facultative anaerobe Salmonella has been extensively studied. Meanwhile, ferroptosis is a newly characterized form of cell death. Nevertheless, the role of ferroptosis in Salmonella-induced tumour cell death remains unclear. Therefore, we aim to elucidate whether Salmonella YB1 exerts therapeutic effects via inducing ferroptosis in glioma. METHODS Following Salmonella YB1 infection, mRNA sequencing was applied to detect ferroptosis-related gene expression and the levels of reactive oxygen species, malondialdehyde, and glutathione were quantified. Transmission electron microscopy (TEM) was then used to observe the changes in the mitochondrial morphology of glioma cells. The role of ferroptosis in the anti-tumor effect of YB1 was assessed in vivo in mouse tumor xenograft models. RESULTS Whole-transcriptome analysis revealed that Salmonella YB1 infection alters ferroptosis-related gene expression in the U87 glioma cell line. Moreover, we found that Salmonella-induced ferroptosis is correlated with reduced levels of glutathione and glutathione peroxidase-4 (GPX4) and increased levels of reactive oxygen species and malondialdehyde in vitro. Meanwhile, TEM revealed that mitochondria are shrunken and mitochondrial membrane density increases in infected glioma cells. Experiments in vivo further showed that tumor growth in the Salmonella-treated group was significantly slower compared to the control and Fer-1 groups. However, Salmonella-induced tumor suppression can be reversed in vivo by Fer-1 treatment. CONCLUSION Salmonella YB1 inhibits GPX4 expression and induces ferroptosis to suppress glioma growth. Hence, ferroptosis regulation might represent a promising strategy to improve the efficacy of bacterial cancer therapy.
Collapse
Affiliation(s)
- Jiawen Chen
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Ting Li
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
- Department of Laboratory Medicine, Clinical Biobank Center, Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Nan Zhou
- ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, 311215, China
| | - Yige He
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong Special Administrative Region, 999077, China
| | - Jiasheng Zhong
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Chengcheng Ma
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Meiqin Zeng
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
- Department of Laboratory Medicine, Clinical Biobank Center, Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Jingsen Ji
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Jian-Dong Huang
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong Special Administrative Region, 999077, China
- Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences (CAS), Chinese Academy of Sciences, Shenzhen, 518055, China
- Clinical Oncology Center, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518055, China
- Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen University, Guangzhou, 510120, China
- Department of Laboratory Medicine, Clinical Biobank Center, Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
| | - Yiquan Ke
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
| | - Haitao Sun
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
- Department of Laboratory Medicine, Clinical Biobank Center, Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
| |
Collapse
|
|
18
|
Zhao W, Lei M, Li J, Zhang H, Zhang H, Han Y, Ba Z, Zhang M, Li D, Liu C. Yes-associated protein inhibition ameliorates liver fibrosis and acute and chronic liver failure by decreasing ferroptosis and necroptosis. Heliyon 2023; 9:e15075. [PMID: 37151632 PMCID: PMC10161368 DOI: 10.1016/j.heliyon.2023.e15075] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 03/23/2023] [Accepted: 03/27/2023] [Indexed: 04/05/2023] Open
Abstract
Background/aims This study aims to determine which cell death modes contribute most in the progression of cirrhosis and acute-on-chronic liver failure (ACLF), and to investigate whether Yes associated protein (YAP) affects the disease process by regulating cell death. Materials and methods 30C57BL/6 male mice were divided into five groups: control, carbon tetrachloride (CCl4)-induced liver fibrosis model, CCl4+verteporfin, CCl4+lipopolysaccharides (LPS) combined with the D-(+)-Galactosamine (LPS/D-GalN)-induced ACLF model, and ACLF + verteporfin. Patients with chronic hepatitis B (CHB), hepatitis B virus (HBV) related liver cirrhosis or ACLF were enrolled. Histology, immunohistochemistry, transmission electron microscopy, Western blot and ELISA were conducted to assess the roles of YAP and cell death in liver cirrhosis and ACLF, and to explore the effect of YAP inhibition on cell deaths. Results YAP was markedly increased in mice with liver fibrosis and ACLF, along with ferroptosis and necroptosis. Furthermore, YAP inhibition significantly suppressed fibrosis in CCl4-mediated liver fibrosis and ACLF-associated liver injury. Notably, CCl4 induced up-regulation of ACSL4 and RIPK3 and down-regulation of SLC7A11, key factors in ferroptosis and necroptosis. This was significantly abrogated by verteporfin treatment. Similar changes in ferroptosis and necroptosis were found in ACLF and ACLF + verteporfin groups. Consistent with the above findings in mice, we found that plasma YAP levels were gradually increased with the development of HBV-related liver fibrosis and ACLF. Conclusion Ferroptosis and necroptosis are involved in the development of liver cirrhosis and ACLF. Inhibition of YAP improved liver fibrosis and liver damage in ACLF through a reduction in ferroptosis and necroptosis. Our findings may help better understanding the role of YAP in liver fibrosis and ACLF.
Collapse
Affiliation(s)
- Wen Zhao
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
- Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China
- Key Laboratory of Infection and Immunity of Anhui Province, China
| | - Miao Lei
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
- Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China
- Key Laboratory of Infection and Immunity of Anhui Province, China
| | - Jinfeng Li
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
- Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China
- Key Laboratory of Infection and Immunity of Anhui Province, China
| | - Hailin Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
- Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China
- Key Laboratory of Infection and Immunity of Anhui Province, China
| | - Hongkun Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
- Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China
- Key Laboratory of Infection and Immunity of Anhui Province, China
| | - Yuxin Han
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
- Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China
- Key Laboratory of Infection and Immunity of Anhui Province, China
| | - Zhiwei Ba
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
- Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China
- Key Laboratory of Infection and Immunity of Anhui Province, China
| | - Manli Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
- Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China
- Key Laboratory of Infection and Immunity of Anhui Province, China
| | - Dongdong Li
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
- Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China
- Key Laboratory of Infection and Immunity of Anhui Province, China
| | - Chuanmiao Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, China
- Core Cooperative Unit of National Clinical Research Center for Infectious Diseases, China
- Key Laboratory of Infection and Immunity of Anhui Province, China
| |
Collapse
|
|
19
|
Kouroumalis E, Tsomidis I, Voumvouraki A. Iron as a therapeutic target in chronic liver disease. World J Gastroenterol 2023; 29:616-655. [PMID: 36742167 PMCID: PMC9896614 DOI: 10.3748/wjg.v29.i4.616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/03/2022] [Accepted: 12/31/2022] [Indexed: 01/20/2023] Open
Abstract
It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease. The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver. In this review, we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin, transferrin, and ferritin in iron homeostasis. The regulation of ferroptosis by endogenous and exogenous mod-ulators will be examined. Furthermore, the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease, chronic hepatitis B and C, liver fibrosis, and hepatocellular carcinoma (HCC) will be analyzed. Finally, experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented. Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC, where induction of ferroptosis is the desired effect. Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.
Collapse
Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71003, Greece
| | - Ioannis Tsomidis
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
| |
Collapse
|
|
20
|
Jia FJ, Han J. Liver injury in COVID-19: Holds ferritinophagy-mediated ferroptosis accountable. World J Clin Cases 2022; 10:13148-13156. [PMID: 36683648 PMCID: PMC9850986 DOI: 10.12998/wjcc.v10.i36.13148] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 11/20/2022] [Accepted: 12/08/2022] [Indexed: 12/26/2022] Open
Abstract
Even in patients without a history of liver disease, liver injury caused by coronavirus disease 2019 (COVID-19) is gradually becoming more common. However, the precise pathophysiological mechanisms behind COVID-19's liver pathogenicity are still not fully understood. We hypothesize that inflammation may become worse by cytokine storms caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Elevated ferritin levels can initiate ferritinophagy mediated by nuclear receptor coactivator 4 (NCOA4), which leads to iron elevation, and ferroptosis. In COVID-19 patients, ferroptosis can be restricted to reduce disease severity and liver damage by targeting NCOA4-mediated ferritinophagy. To confirm the role of ferritinophagy-mediated ferroptosis in SARS-CoV-2 infection, further research is required.
Collapse
Affiliation(s)
- Feng-Ju Jia
- School of Nursing, Qingdao University, Qingdao 266071, Shandong Province, China
| | - Jing Han
- School of Nursing, Qingdao University, Qingdao 266071, Shandong Province, China
| |
Collapse
|
|
21
|
Zheng X, Wang Q, Zhou Y, Zhang D, Geng Y, Hu W, Wu C, Shi Y, Jiang J. N-acetyltransferase 10 promotes colon cancer progression by inhibiting ferroptosis through N4-acetylation and stabilization of ferroptosis suppressor protein 1 (FSP1) mRNA. CANCER COMMUNICATIONS (LONDON, ENGLAND) 2022; 42:1347-1366. [PMID: 36209353 PMCID: PMC9759759 DOI: 10.1002/cac2.12363] [Citation(s) in RCA: 94] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 05/18/2022] [Accepted: 09/15/2022] [Indexed: 01/25/2023]
Abstract
BACKGROUND N-acetyltransferase 10 (NAT10) is the only enzyme known to mediate the N4-acetylcytidine (ac4C) modification of mRNA and is crucial for mRNA stability and translation efficiency. However, its role in cancer development and prognosis has not yet been explored. This study aimed to examine the possible role of NAT10 in colon cancer. METHODS The expression levels of NAT10 were evaluated by immunohistochemical analyses with a colon cancer tissue microarray, and its prognostic value in patients was further analyzed. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were performed to analyze NAT10 expression in harvested colon cancer tissues and cell lines. Stable NAT10-knockdown and NAT10-overexpressing colon cancer cell lines were constructed using lentivirus. The biological functions of NAT10 in colon cancer cell lines were analyzed in vitro by Cell Counting Kit-8 (CCK-8), wound healing, Transwell, cell cycle, and ferroptosis assays. Xenograft models were used to analyze the effect of NAT10 on the tumorigenesis and metastasis of colon cancer cells in vivo. Dot blotting, acetylated RNA immunoprecipitation-qPCR, and RNA stability analyses were performed to explore the mechanism by which NAT10 functions in colon cancer progression. RESULTS NAT10 was upregulated in colon cancer tissues and various colon cancer cell lines. This increased NAT10 expression was associated with shorter patient survival. Knockdown of NAT10 in two colon cancer cell lines (HT-29 and LoVo) impaired the proliferation, migration, invasion, tumor formation and metastasis of these cells, whereas overexpression of NAT10 promoted these abilities. Further analysis revealed that NAT10 exerted a strong effect on the mRNA stability and expression of ferroptosis suppressor protein 1 (FSP1) in HT-29 and LoVo cells. In these cells, FSP1 mRNA was found to be modified by ac4C acetylation, and this epigenetic modification was associated with the inhibition of ferroptosis. CONCLUSIONS Our study revealed that NAT10 plays a critical role in colon cancer development by affecting FSP1 mRNA stability and ferroptosis, suggesting that NAT10 could be a novel prognostic and therapeutic target in colon cancer.
Collapse
Affiliation(s)
- Xiao Zheng
- Department of Tumor Biological Treatmentthe Third Affiliated Hospital of Soochow UniversityChangzhouJiangsu213003P. R. China,Jiangsu Engineering Research Center for Tumor ImmunotherapyChangzhouJiangsu213003P. R. China,Institute for Cell Therapy of Soochow UniversityChangzhouJiangsu213003P. R. China
| | - Qi Wang
- Department of Tumor Biological Treatmentthe Third Affiliated Hospital of Soochow UniversityChangzhouJiangsu213003P. R. China,Jiangsu Engineering Research Center for Tumor ImmunotherapyChangzhouJiangsu213003P. R. China,Institute for Cell Therapy of Soochow UniversityChangzhouJiangsu213003P. R. China
| | - You Zhou
- Department of Tumor Biological Treatmentthe Third Affiliated Hospital of Soochow UniversityChangzhouJiangsu213003P. R. China,Jiangsu Engineering Research Center for Tumor ImmunotherapyChangzhouJiangsu213003P. R. China,Institute for Cell Therapy of Soochow UniversityChangzhouJiangsu213003P. R. China
| | - Dachuan Zhang
- Department of Pathologythe Third Affiliated Hospital of Soochow UniversityChangzhouJiangsu213003P. R. China
| | - Yiting Geng
- Jiangsu Engineering Research Center for Tumor ImmunotherapyChangzhouJiangsu213003P. R. China,Department of Oncologythe Third Affiliated Hospital of Soochow UniversityChangzhouJiangsu213003P. R. China
| | - Wenwei Hu
- Jiangsu Engineering Research Center for Tumor ImmunotherapyChangzhouJiangsu213003P. R. China,Department of Oncologythe Third Affiliated Hospital of Soochow UniversityChangzhouJiangsu213003P. R. China
| | - Changping Wu
- Department of Tumor Biological Treatmentthe Third Affiliated Hospital of Soochow UniversityChangzhouJiangsu213003P. R. China,Jiangsu Engineering Research Center for Tumor ImmunotherapyChangzhouJiangsu213003P. R. China,Department of Oncologythe Third Affiliated Hospital of Soochow UniversityChangzhouJiangsu213003P. R. China
| | - Yufang Shi
- Department of Tumor Biological Treatmentthe Third Affiliated Hospital of Soochow UniversityChangzhouJiangsu213003P. R. China,Jiangsu Engineering Research Center for Tumor ImmunotherapyChangzhouJiangsu213003P. R. China,Institute for Translational Medicine of Soochow UniversitySuzhouJiangsu215000P. R. China,CAS Key Laboratory of Tissue Microenvironment and TumorShanghai Institute of Nutrition and HealthUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai200031P. R. China
| | - Jingting Jiang
- Department of Tumor Biological Treatmentthe Third Affiliated Hospital of Soochow UniversityChangzhouJiangsu213003P. R. China,Jiangsu Engineering Research Center for Tumor ImmunotherapyChangzhouJiangsu213003P. R. China,Institute for Cell Therapy of Soochow UniversityChangzhouJiangsu213003P. R. China,State Key Laboratory of Pharmaceutical BiotechnologyNanjing UniversityNanjingJiangsu210023P. R. China
| |
Collapse
|
|
22
|
Wang Z, Li H, Zhou W, Lee J, Liu Z, An Z, Xu D, Mo H, Hu L, Zhou X. Ferrous sulfate-loaded hydrogel cures Staphylococcus aureus infection via facilitating a ferroptosis-like bacterial cell death in a mouse keratitis model. Biomaterials 2022; 290:121842. [DOI: 10.1016/j.biomaterials.2022.121842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 09/02/2022] [Accepted: 09/27/2022] [Indexed: 11/02/2022]
|
|
23
|
Dorninger F, Werner ER, Berger J, Watschinger K. Regulation of plasmalogen metabolism and traffic in mammals: The fog begins to lift. Front Cell Dev Biol 2022; 10:946393. [PMID: 36120579 PMCID: PMC9471318 DOI: 10.3389/fcell.2022.946393] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 07/25/2022] [Indexed: 12/15/2022] Open
Abstract
Due to their unique chemical structure, plasmalogens do not only exhibit distinct biophysical and biochemical features, but require specialized pathways of biosynthesis and metabolization. Recently, major advances have been made in our understanding of these processes, for example by the attribution of the gene encoding the enzyme, which catalyzes the final desaturation step in plasmalogen biosynthesis, or by the identification of cytochrome C as plasmalogenase, which allows for the degradation of plasmalogens. Also, models have been presented that plausibly explain the maintenance of adequate cellular levels of plasmalogens. However, despite the progress, many aspects around the questions of how plasmalogen metabolism is regulated and how plasmalogens are distributed among organs and tissues in more complex organisms like mammals, remain unresolved. Here, we summarize and interpret current evidence on the regulation of the enzymes involved in plasmalogen biosynthesis and degradation as well as the turnover of plasmalogens. Finally, we focus on plasmalogen traffic across the mammalian body - a topic of major importance, when considering plasmalogen replacement therapies in human disorders, where deficiencies in these lipids have been reported. These involve not only inborn errors in plasmalogen metabolism, but also more common diseases including Alzheimer's disease and neurodevelopmental disorders.
Collapse
Affiliation(s)
- Fabian Dorninger
- Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, Austria,*Correspondence: Fabian Dorninger, ; Katrin Watschinger,
| | - Ernst R. Werner
- Institute of Biological Chemistry, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Johannes Berger
- Department of Pathobiology of the Nervous System, Center for Brain Research, Medical University of Vienna, Vienna, Austria
| | - Katrin Watschinger
- Institute of Biological Chemistry, Biocenter, Medical University of Innsbruck, Innsbruck, Austria,*Correspondence: Fabian Dorninger, ; Katrin Watschinger,
| |
Collapse
|
|
24
|
Lv Y, Feng Q, Zhang Z, Zheng P, Zhu D, Lin Q, Chen S, Mao Y, Xu Y, Ji M, Xu J, He G. Low ferroptosis score predicts chemotherapy responsiveness and immune-activation in colorectal cancer. Cancer Med 2022; 12:2033-2045. [PMID: 35855531 PMCID: PMC9883409 DOI: 10.1002/cam4.4956] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 01/19/2022] [Accepted: 02/06/2022] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND Existing studies for ferroptosis and prognosis in colorectal cancer (CRC) were limited. In this study, we aim to investigate the prognostic role of ferroptosis markers in patients with CRC and exploration of its micro-environmental distributions. METHODS Immunohistochemical staining was performed for CRC patients' tissue microarray. Selection and prognostic validation of markers were based on mRNA data from the cancer genome atlas (TCGA) database. Gene Set Enrichment Analysis (GSEA) was performed to indicate relative immune landmarks and hallmarks. Ferroptosis and immune contexture were examined by CIBERSORT. Survival outcomes were analyzed by Kaplan-Meier analysis and cox analysis. RESULTS A panel of 42 genes was selected. Through mRNA expression difference and prognosis analysis, GPX4, NOX1 and ACSL4 were selected as candidate markers. By IHC, increased GPX4, decreased NOX1 and decreased FACL4 indicate poor prognosis and worse clinical characteristics. Ferroptosis score based on GPX4, NOX1 and ACSL4 was constructed and validated with high C-index. Low ferroptosis score can also demonstrate the better progression free survival and better adjuvant chemotherapy (ACT) responsiveness. Moreover, tumor with low ferroptosis score tend to be infiltrated with more CD4+ T cells, CD8+ T cells and less M1 macrophage. Finally, we found that IFN-γ was potentially the central molecule at the crossroad between ferroptosis and onco-immune response. CONCLUSION Ferroptosis plays important role on CRC tumor progression, ACT response and prognosis. Ferroptosis contributes to immune-supportive responses and IFN-γ was the central molecule for this process.
Collapse
Affiliation(s)
- Yang Lv
- Department of General SurgeryZhongshan Hospital, Fudan UniversityShanghaiChina,Colorectal Cancer CenterZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Qing‐Yang Feng
- Department of General SurgeryZhongshan Hospital, Fudan UniversityShanghaiChina,Colorectal Cancer CenterZhongshan Hospital, Fudan UniversityShanghaiChina,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive SurgeryShanghaiChina
| | - Zhi‐Yuan Zhang
- Department of General SurgeryZhongshan Hospital, Fudan UniversityShanghaiChina,Colorectal Cancer CenterZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Peng Zheng
- Department of General SurgeryZhongshan Hospital, Fudan UniversityShanghaiChina,Colorectal Cancer CenterZhongshan Hospital, Fudan UniversityShanghaiChina,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive SurgeryShanghaiChina
| | - De‐xiang Zhu
- Department of General SurgeryZhongshan Hospital, Fudan UniversityShanghaiChina,Colorectal Cancer CenterZhongshan Hospital, Fudan UniversityShanghaiChina,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive SurgeryShanghaiChina
| | - Qi Lin
- Department of General SurgeryZhongshan Hospital, Fudan UniversityShanghaiChina,Colorectal Cancer CenterZhongshan Hospital, Fudan UniversityShanghaiChina,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive SurgeryShanghaiChina
| | - Si‐min Chen
- Department of PathologyAffiliated Hospital of Nanjing University of Chinese MedicineNanjingJiangsuChina
| | - Yi‐Hao Mao
- Department of General SurgeryZhongshan Hospital, Fudan UniversityShanghaiChina,Colorectal Cancer CenterZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Yu‐Qiu Xu
- Department of General SurgeryZhongshan Hospital, Fudan UniversityShanghaiChina,Colorectal Cancer CenterZhongshan Hospital, Fudan UniversityShanghaiChina
| | - Mei‐ling Ji
- Department of General SurgeryZhongshan Hospital, Fudan UniversityShanghaiChina,Colorectal Cancer CenterZhongshan Hospital, Fudan UniversityShanghaiChina,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive SurgeryShanghaiChina
| | - Jian‐Min Xu
- Department of General SurgeryZhongshan Hospital, Fudan UniversityShanghaiChina,Colorectal Cancer CenterZhongshan Hospital, Fudan UniversityShanghaiChina,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive SurgeryShanghaiChina
| | - Guo‐dong He
- Department of General SurgeryZhongshan Hospital, Fudan UniversityShanghaiChina,Colorectal Cancer CenterZhongshan Hospital, Fudan UniversityShanghaiChina,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive SurgeryShanghaiChina
| |
Collapse
|
|
25
|
Andreani C, Bartolacci C, Scaglioni PP. Ferroptosis: A Specific Vulnerability of RAS-Driven Cancers? Front Oncol 2022; 12:923915. [PMID: 35912247 PMCID: PMC9337859 DOI: 10.3389/fonc.2022.923915] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 05/03/2022] [Indexed: 12/11/2022] Open
Abstract
Ferroptosis has emerged as a new type of programmed cell death that can be harnessed for cancer therapy. The concept of ferroptosis was for the first time proposed in in the early 2000s, as an iron-dependent mode of regulated cell death caused by unrestricted lipid peroxidation (LPO) and subsequent plasma membrane rupture. Since the discovery and characterization of ferroptosis, a wealth of research has improved our understanding of the main pathways regulating this process, leading to both the repurposing and the development of small molecules. However, ferroptosis is still little understood and several aspects remain to be investigated. For instance, it is unclear whether specific oncogenes, cells of origin or tumor niches impose specific susceptibility/resistance to ferroptosis or if there are some ferroptosis-related genes that may be used as bona fide pan-cancer targetable dependencies. In this context, even though RAS-driven cancer cell lines seemed to be selectively sensitive to ferroptosis inducers, subsequent studies have questioned these results, indicating that in some cases mutant RAS is necessary, but not sufficient to induce ferroptosis. In this perspective, based on publicly available genomic screening data and the literature, we discuss the relationship between RAS-mutation and ferroptosis susceptibility in cancer.
Collapse
Affiliation(s)
| | | | - Pier Paolo Scaglioni
- Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| |
Collapse
|
|
26
|
Zhou X, Fu Y, Liu W, Mu Y, Zhang H, Chen J, Liu P. Ferroptosis in Chronic Liver Diseases: Opportunities and Challenges. Front Mol Biosci 2022; 9:928321. [PMID: 35720113 PMCID: PMC9205467 DOI: 10.3389/fmolb.2022.928321] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 05/16/2022] [Indexed: 01/01/2023] Open
Abstract
Ferroptosis, an iron-dependent non-apoptotic cell death characterized by lipid peroxidation, is a cell death pathway discovered in recent years. Ferroptosis plays an important role in tumors, ischemia-reperfusion injury, neurological diseases, blood diseases, etc. Recent studies have shown the importance of ferroptosis in chronic liver disease. This article summarizes the pathological mechanisms of ferroptosis involved in System Xc-, iron metabolism, lipid metabolism, and some GPX4-independent pathways, and the latest research on ferroptosis in chronic liver diseases such as alcoholic liver disease, non-alcoholic fatty liver disease, liver fibrosis, hepatocellular carcinoma. In addition, the current bottleneck issues that restrict the research on ferroptosis are proposed to provide ideas and strategies for exploring new therapeutic targets for chronic liver diseases.
Collapse
Affiliation(s)
- Xiaoxi Zhou
- Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Yadong Fu
- Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
- Institute of Interdisciplinary Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China
| | - Wei Liu
- Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Yongping Mu
- Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Hua Zhang
- Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Jiamei Chen
- Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Ping Liu
- Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
- Institute of Interdisciplinary Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| |
Collapse
|
|
27
|
Yang L, WenTao T, ZhiYuan Z, Qi L, YuXiang L, Peng Z, Ke L, XiaoNa J, YuZhi P, MeiLing J, QingYang F, GuoDong H, YueXiang W, JianMin X. Cullin-9/p53 mediates HNRNPC degradation to inhibit erastin-induced ferroptosis and is blocked by MDM2 inhibition in colorectal cancer. Oncogene 2022; 41:3210-3221. [PMID: 35505093 DOI: 10.1038/s41388-022-02284-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 02/27/2022] [Accepted: 03/17/2022] [Indexed: 01/05/2023]
Abstract
Colorectal cancer (CRC) is the leading cause of cancer associated death worldwide. Ferroptosis is a newly defined form of regulated cell death characterized by the accumulation of lipid hydroperoxides and exerts an increased attention for cancer treatment. However, little is known about ferroptosis in CRC. In this study, through whole genome sequencing and external differential differentiated expression analysis, we identify CUL9 as a novel important modulator for ferroptosis in CRC. Here we demonstrated that CUL9 can binds p53 to ubiquitylate heterogeneous nuclear ribonucleoprotein C for degradation. Overexpression of CUL9 increases resistance to erastin-induced ferroptosis. Then, we discovered this resistance was mediated by CUL9-HNRNPC-MATE1 negative loop, which can provide us with a novel target to overcome drug resistance to ferroptosis activators. Finally, we found that targeting MDM2 was developed as an effective strategy to destroy precious drug-resistant CRC cells.
Collapse
Affiliation(s)
- Lv Yang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tang WenTao
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive Surgery, Shanghai, China
| | - Zhang ZhiYuan
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive Surgery, Shanghai, China
| | - Lin Qi
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive Surgery, Shanghai, China
| | - Luo YuXiang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Zheng Peng
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive Surgery, Shanghai, China
| | - Li Ke
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Jia XiaoNa
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Pang YuZhi
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Ji MeiLing
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive Surgery, Shanghai, China
| | - Feng QingYang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive Surgery, Shanghai, China
| | - He GuoDong
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.,Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive Surgery, Shanghai, China
| | - Wang YueXiang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
| | - Xu JianMin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. .,Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China. .,Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive Surgery, Shanghai, China.
| |
Collapse
|
|
28
|
Fernández-García V, González-Ramos S, Avendaño-Ortiz J, Martín-Sanz P, Delgado C, Castrillo A, Boscá L. NOD1 splenic activation confers ferroptosis protection and reduces macrophage recruitment under pro-atherogenic conditions. Biomed Pharmacother 2022; 148:112769. [PMID: 35247718 DOI: 10.1016/j.biopha.2022.112769] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 02/15/2022] [Accepted: 02/27/2022] [Indexed: 02/07/2023] Open
Abstract
The bioavailability and regulation of iron is essential for central biological functions in mammals. The role of this element in ferroptosis and the dysregulation of its metabolism contribute to diseases, ranging from anemia to infections, alterations in the immune system, inflammation and atherosclerosis. In this sense, monocytes and macrophages modulate iron metabolism and splenic function, while at the same time they can worsen the atherosclerotic process in pathological conditions. Since the nucleotide-binding oligomerization domain 1 (NOD1) has been linked to numerous disorders, including inflammatory and cardiovascular diseases, we investigated its role in iron homeostasis. The iron content was measured in various tissues of Apoe-/- and Apoe-/-Nod1-/- mice fed a high-fat diet (HFD) for 4 weeks, under normal or reduced splenic function after ligation of the splenic artery. In the absence of NOD1 the iron levels decreased in spleen, heart and liver regardless the splenic function. This iron decrease was accompanied by an increase in the recruitment of F4/80+-macrophages in the spleen through a CXCR2-dependent signaling, as deduced by the reduced recruitment after administration of a CXCR2 inhibitor. CXCR2 mediates monocyte/macrophage chemotaxis to areas of inflammation and accumulation of leukocytes in the atherosclerotic plaque. Moreover, in the absence of NOD1, inhibition of CXCR2 enhanced atheroma progression. NOD1 activation increased the levels of GPX4 and other iron and ferroptosis regulatory proteins in macrophages. Our findings highlight the preeminent role of NOD1 in iron homeostasis and ferroptosis. These results suggest promising avenues of investigation for the diagnosis and treatment of iron-related diseases directed by NOD1.
Collapse
Affiliation(s)
- Victoria Fernández-García
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, Madrid 28029, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Monforte de Lemos 3-5, Madrid 28029, Spain.
| | - Silvia González-Ramos
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, Madrid 28029, Spain
| | - José Avendaño-Ortiz
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz, IdiPAZ. Pedro Rico, 6, Madrid 28029, Spain
| | - Paloma Martín-Sanz
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, Madrid 28029, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, Madrid 28029, Spain
| | - Carmen Delgado
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, Madrid 28029, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Monforte de Lemos 3-5, Madrid 28029, Spain
| | - Antonio Castrillo
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, Madrid 28029, Spain; Unidad de Biomedicina (Unidad Asociada al CSIC), Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS) de la Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain
| | - Lisardo Boscá
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, Madrid 28029, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Monforte de Lemos 3-5, Madrid 28029, Spain.
| |
Collapse
|
|
29
|
Zhou A, Fang T, Chen K, Xu Y, Chen Z, Ning X. Biomimetic Activator of Sonodynamic Ferroptosis Amplifies Inherent Peroxidation for Improving the Treatment of Breast Cancer. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2106568. [PMID: 35092152 DOI: 10.1002/smll.202106568] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/24/2021] [Indexed: 06/14/2023]
Abstract
Ferroptosis is a type of nonapoptotic cell death and is gradually emerging as an important anticancer treatment. However, its therapeutic efficacy is impaired by low intracellular levels of reactive oxygen species (ROS) and long-chain polyunsaturated fatty acids, significantly limiting its therapeutic potential. Herein, a multimodal strategy to improve ferroptosis is presented, in which a state-of-art engineered erythrocyte, termed as sonodynamic amplified ferroptosis erythrocyte (SAFE), is developed for simultaneously activating ferroptosis and oxygen-riched sonodynamic therapy (SDT). SAFE is composed of internalizing RGD peptide and red blood cell membrane hybrid camouflaged nanocomplex of hemoglobin, perfluorocarbon, ferroptosis activator (dihomo-γ-linolenic acid, DGLA), and sonosensitizer verteporfin. It is identified that SAFE, under ultrasound stimulation, can not only substantially supply oxygen to overcome tumor hypoxia associated therapeutic resistance, but effectively activate ferroptosis through the coeffect of SDT triggered ROS production and DGLA mediated lipid peroxidation. In vivo studies reveal that SAFE selectively accumulates in tumor tissues and induces desirable anticancer effects under mild ultrasound stimulation. Importantly, SAFE can effectively inhibit tumor growth with minimal invasiveness, resulting in a prolonged survival period of mice. Therefore, a multimodal ferroptosis therapy driven by oxygen-riched sonodynamic peroxidation of lipids, significantly advancing synergistic cancer treatment, is presented.
Collapse
Affiliation(s)
- Anwei Zhou
- Jiangsu Province Nanjing, Qixia District, Xianlin Road No. 163, Nanjing, 210093, China
- National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, School of Physics, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing, 210093, China
| | - Tianliang Fang
- Department of Pharmacology, Molecular Cancer Research Center, School of Medicine, Sun Yat-Sen University, Guangzhou, 510008, China
| | - Kerong Chen
- Jiangsu Province Nanjing, Qixia District, Xianlin Road No. 163, Nanjing, 210093, China
- National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing, 210093, China
| | - Yurui Xu
- Jiangsu Province Nanjing, Qixia District, Xianlin Road No. 163, Nanjing, 210093, China
- National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing, 210093, China
| | - Zhuo Chen
- Jiangsu Province Nanjing, Qixia District, Xianlin Road No. 163, Nanjing, 210093, China
- National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, School of Physics, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing, 210093, China
| | - Xinghai Ning
- Jiangsu Province Nanjing, Qixia District, Xianlin Road No. 163, Nanjing, 210093, China
- National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, Chemistry and Biomedicine Innovation Center, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing, 210093, China
| |
Collapse
|
|
30
|
Rodriguez R, Schreiber SL, Conrad M. Persister cancer cells: Iron addiction and vulnerability to ferroptosis. Mol Cell 2022; 82:728-740. [PMID: 34965379 PMCID: PMC9152905 DOI: 10.1016/j.molcel.2021.12.001] [Citation(s) in RCA: 151] [Impact Index Per Article: 50.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 11/17/2021] [Accepted: 12/01/2021] [Indexed: 12/11/2022]
Abstract
Ferroptosis is a unique type of non-apoptotic cell death resulting from the unrestrained occurrence of peroxidized phospholipids, which are subject to iron-mediated production of lethal oxygen radicals. This cell death modality has been detected across many organisms, including in mammals, where it can be used as a defense mechanism against pathogens or even harnessed by T cells to sensitize tumor cells toward effective killing. Conversely, ferroptosis is considered one of the main cell death mechanisms promoting degenerative diseases. Emerging evidence suggests that ferroptosis represents a vulnerability in certain cancers. Here, we critically review recent advances linking ferroptosis vulnerabilities of dedifferentiating and persister cancer cells to the dependency of these cells on iron, a potential Achilles heel for small-molecule intervention. We provide a perspective on the mechanisms reliant on iron that contribute to the persister cancer cell state and how this dependency may be exploited for therapeutic benefits.
Collapse
Affiliation(s)
- Raphaël Rodriguez
- Chemical Biology of Cancer at Institut Curie, PSL Research University, CNRS UMR 3666, INSERM U1143, Paris, France.
| | - Stuart L Schreiber
- Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
| | - Marcus Conrad
- Institute of Metabolism and Cell Death, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Pirogov National Research Medical University, Laboratory of Experimental Oncology, Moscow 117997, Russia.
| |
Collapse
|
|
31
|
Abstract
Ferroptosis is an iron-dependent form of regulated cell death, which is characterized by a large amount of lipid peroxide accumulation and the imbalance of redox state in cells. Ferroptosis is usually accompanied with the dysfunction of lipid repair enzyme (glutathione peroxidase 4, GPX4), large masses of iron accumulation and lipid peroxidation of polyunsaturated fatty acids (PUFAs). Ferroptosis is related to several signaling pathways, including amino acid and iron metabolism, ferritinophagy, cell adhesion and p53 and Keap1/Nrf2 signaling pathways. A number of studies have indicated that ferroptosis is closely associated with acute renal failure, tumor, ischemia and reperfusion injury, neurodegenerative diseases and liver fibrosis. Liver fibrosis, which has long been a global health problem, still lacks effective treatment till now, and the discovery of ferroptosis provides a new insight into addressing this issue.
Collapse
Affiliation(s)
| | | | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kang He
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
32
|
Perez MA, Watts JL. Worms, Fat, and Death: Caenorhabditis elegans Lipid Metabolites Regulate Cell Death. Metabolites 2021; 11:metabo11020125. [PMID: 33672292 PMCID: PMC7926963 DOI: 10.3390/metabo11020125] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/19/2021] [Accepted: 02/19/2021] [Indexed: 12/28/2022] Open
Abstract
Caenorhabditis elegans is well-known as the model organism used to elucidate the genetic pathways underlying the first described form of regulated cell death, apoptosis. Since then, C. elegans investigations have contributed to the further understanding of lipids in apoptosis, especially the roles of phosphatidylserines and phosphatidylinositols. More recently, studies in C. elegans have shown that dietary polyunsaturated fatty acids can induce the non-apoptotic, iron-dependent form of cell death, ferroptosis. In this review, we examine the roles of various lipids in specific aspects of regulated cell death, emphasizing recent work in C. elegans.
Collapse
|