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AZD1775 synergizes with SLC7A11 inhibition to promote ferroptosis

Science China Life Sciences 2025年第01期 204-218页

作者： Chen Xiong Hong Ling Yingdan Huang Hanzhi Dong Bangxiang Xie Qian Hao Xiang Zhou Fudan University Shanghai cancer Center and institutes of Biomedical Sciences Fudan University department of oncology Shanghai Medical CollegeFudan University department of Breast Surgery Fudan University Shanghai Cancer CenterFudan University department of oncology First Affiliated Hospital of Nanchang University Beijing Institute of Hepatology Beijing Youan HospitalCapital Medical University Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver cancer Key Laboratory of Breast cancer in Shanghai Fudan University Shanghai Cancer CenterFudan University Shanghai Key Laboratory of Medical Epigenetics International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology)Institutes of Biomedical SciencesFudan University

Tumor suppressor p53-mediated cell cycle arrest and DNA damage repair may exert cytoprotective effects against cancer therapies, including WEE1 inhibition. Considering that p53 activation can also lead to multiple types of cell death, the role of this tumor suppressor in WEE1 inhibitor-based therapies remains disputed. In this study, we reported that nucleolar stress-mediated p53 activation enhanced the WEE1 inhibitor AZD1775-induced ferroptosis to suppress lung cancer growth. Our findings showed that AZD1775 promoted ferroptosis by blocking cystine uptake, an action similar to that of Erastin. Meanwhile, inhibition of WEE1 by the WEE1 inhibitors or si RNAs induced compensatory upregulation of SLC7A11, which conferred resistance to ferroptosis. Mechanistically, AZD1775 prevented the enrichment of H3K9me3, a histone marker of transcriptional repression, on the SLC7A11 promoter by repressing the expression of the histone methyltransferase SETDB1, thereby enhancing NRF2-mediated SLC7A11 transcription. This finding was also validated using the H3K9me3 inhibitor BRD4770. Remarkably, we found that the nucleolar stress-inducing agent Actinomycin D(Act. D) inhibited SLC7A11 expression by activating p53, thus augmenting AZD1775-induced ferroptosis. Moreover, the combination of AZD1775 and Act. D synergistically suppressed wild-type p53-harboring lung cancer cell growth both in vitro and in vivo. Altogether, our study demonstrates that AZD1775 promotes ferroptosis by targeting cystine uptake but also mediates the adaptive activation of SLC7A11 through the WEE1-SETDB1 cascade and NRF2-induced transcription, and inhibition of SLC7A11 by Act. D boosts the anti-tumor efficacy of AZD1775 by enhancing ferroptosis in cancers with wild-type p53.

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Regulation of androgen receptor variants in prostate cancer

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Asian Journal of Urology 2020年第3期7卷 251-257页

作者： Yezi Zhu Jun Luo department of Urology James Buchanan Brady Urological InstituteJohns Hopkins UniversityBaltimoreMDUSA livestrong cancer institutes The University of TexasAustinTXUSA

Aberrant activation of androgen receptor(AR)signaling occurs in patients treated with AR-targeted therapies,contributing to the development of castration-resistant prostate cancer(CRPC)and therapeutic *** the past decade,many AR variants(AR-Vs)have been identified in prostate cancer cell lines and clinical CRPC *** AR-Vs lack the COOH-terminal ligand-binding domain(LBD),and may mediate constitutively active AR signaling acquired following AR-targeting *** splice variant-7(AR-V7),one of the most well characterized AR-Vs,can be reliably measured in tissue and liquid biopsy specimens,and blood-based detection of AR-V7 is a reliable indicator of poor outcome to relatively novel hormonal therapies(NHT)such as abiraterone and enzalutamide in men with metastatic CRPC(mCRPC).Given the important clinical implication of AR-Vs,this short review will focus on studies addressing how AR-Vs are regulated in prostate *** regard to the molecular origin of AR-Vs,it is established that expression of AR-Vs is highly correlated with androgen deprivation and suppression of AR *** targeting of the AR axis may result in active transcription of the AR gene,elevated activities of certain components of the mRNA splicing machinery,as well as AR genomic alterations,all of which may explain the molecular origin of *** a unified hypothesis is currently lacking,existing data suggest that elevated expression of AR-Vs,which in general occurs quite specifically in a cellular environment where the canonical AR signaling is suppressed,is driven by both genomic and epigenomic features acquired in the development of CRPC.

关键词： Androgen receptor Androgen receptor splice variant-7 Castration-resistant prostate cancer

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Correlation between gut microbiota and tumor immune microenvironment:A bibliometric and visualized study

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World Journal of Clinical oncology 2025年第2期16卷 110-129页

作者： Zheng-Jun Hu Hui-Rong Zhu Yong-Jie Jin Pan Liu Xiao-Wei Yu Yu-Ren Zhang department of oncology Shanghai Jiading District Hospital of Traditional Chinese MedicineShanghai 200000China department of oncology Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghai 200000China School of Chinese Medicine Anhui University of Traditional Chinese MedicineHefei 230000Anhui ProvinceChina

BACKGROUND In recent years,numerous reports have been published regarding the relationship between the gut microbiota and the tumor immune microenvironment(TIME).However,to date,no systematic study has been conducted on the relationship between gut microbiota and the TIME using bibliometric *** To describe the current global research status on the correlation between gut microbiota and the TIME,and to identify the most influential countries,research institutions,researchers,and research hotspots related to this *** We searched for all literature related to gut microbiota and TIME published from January 1,2014,to May 28,2024,in the Web of Science Core Collection *** then conducted a bibliometric analysis and created visual maps of the published literature on countries,institutions,authors,keywords,references,etc.,using CiteSpace(6.2R6),VOSviewer(1.6.20),and bibliometrics(based on R 4.3.2).RESULTS In total,491 documents were included,with a rapid increase in the number of publications starting in *** country with the highest number of publications was China,followed by the United *** has the highest number of citations in *** a centrality perspective,the United States has the highest influence in this *** institutions with the highest number of publications were Shanghai Jiao Tong University and Zhejiang ***,the institution with the most citations was the United States National cancer *** authors,Professor Giorgio Trinchieri from the National institutes of Health has the most local impact in this *** most cited author was Fan *** results of journal publications showed that the top three journals with the highest number of published papers were Frontiers in Immunology,cancers,and Frontiers in *** three most frequently used keywords were gut microbiota,tumor microenvironment,and *** This study systematically elaborates on the research progress re

关键词： Gut microbiota Tumor immune microenvironment Bibliometric CiteSpace VOSviewer R-bibliometrics

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Dietary folate drives methionine metabolism to promote cancer development by stabilizing MAT IIA

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Signal Transduction and Targeted Therapy 2022年第7期7卷 2581-2592页

作者： Jin-Tao Li Hai Yang Ming-Zhu Lei Wei-Ping Zhu Ying Su Kai-Yue Li Wen-Ying Zhu Jian Wang Lei Zhang Jia Qu Lei Lv Hao-Jie Lu Zheng-Jun Chen Lu Wang Miao Yin Qun-Ying Lei Fudan University Shanghai cancer Center&institutes of Biomedical Sciences cancer institutes Key Laboratory of Breast cancer in Shanghai Shanghai Key Laboratory of Radiation oncology the Shanghai Key Laboratory of Medical EpigeneticsDepartment of OncologyShanghai Medical CollegeFudan UniversityShanghai 200032People’s Republic of China department of Hepatic Surgery Fudan University Shanghai Cancer CenterShanghai Medical CollegeFudan UniversityShanghai 200032People’s Republic of China

Folic acid,served as dietary supplement,is closely linked to one-carbon metabolism and methionine *** clinical evidence indicated that folic acid supplementation displays dual effect on cancer development,promoting or suppressing tumor formation and ***,the underlying mechanism remains to be ***,we report that high-folate diet significantly promotes cancer development in mice with hepatocellular carcinoma(HCC)induced by DEN/high-fat diet(HFD),simultaneously with increased expression of methionine adenosyltransferase 2A(gene name,MAT2A;protein name,MATIIα),the key enzyme in methionine metabolism,and acceleration of methionine cycle in cancer *** contrast,folate-free diet reduces MATIIαexpression and impedes HFD-induced HCC ***,methionine metabolism is dynamically reprogrammed with valosin-containing protein p97/p47 complex-interacting protein(VCIP135)which functions as a deubiquitylating enzyme to bind and stabilize MATIIαin response to folic acid ***,upregulation of MATIIαexpression is positively correlated with increased VCIP135 protein level in human HCC tissues compared to adjacent ***,liver-specific knockout of Mat2a remarkably abolishes the advocating effect of folic acid on HFD-induced HCC,demonstrating that the effect of high or free folate-diet on HFD-induced HCC relies on ***,folate and multiple intermediate metabolites in one-carbon metabolism are significantly decreased in vivo and in vitro upon Mat2a ***,folate promotes the integration of methionine and one-carbon metabolism,contributing to HCC development via hijacking MATIIαmetabolic *** study provides insight into folate-promoted cancer development,strongly recommending the tailor-made folate supplement guideline for both sub-healthy populations and patients with cancer expressing high level of MATIIαexpression.

关键词： metabolism cancer methionine

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Palmitoylation of MDH2 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth

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Science China(Life Sciences) 2022年第10期65卷 2017-2030页

作者： Xuan Pei Kai-Yue Li Yuan Shen Jin-Tao Li Ming-Zhu Lei Cai-Yun Fang Hao-Jie Lu Hui-Juan Yang Wenyu Wen Miao Yin Jia Qu Qun-Ying Lei Fudan University Shanghai cancer Center&institutes of Biomedical Sciences Cancer InstitutesKey Laboratory of Breast Cancer in ShanghaiShanghai Key Laboratory of Radiation OncologyThe Shanghai Key Laboratory of Medical EpigeneticsShanghai Medical CollegeFudan UniversityShanghai 200032China department of oncology Shanghai Medical CollegeFudan UniversityShanghai 200032China department of Gynecological oncology Fudan University Shanghai Cancer CenterShanghai 200032China State Key Laboratory of Medical Neurobiology Fudan UniversityShanghai 200032China

Epithelial ovarian cancer(EOC) exhibits strong dependency on the tricarboxylic acid(TCA) cycle and oxidative phosphorylation to fuel anabolic ***,we show that malate dehydrogenase 2(MDH2),a key enzyme of the TCA cycle,is palmitoylated at cysteine 138(C138) residue,resulting in increased activity of *** next identify that ZDHHC18 acts as a palmitoyltransferase of *** deprivation enhances MDH2 palmitoylation by increasing the binding between ZDHHC18 and ***2 silencing represses mitochondrial respiration as well as ovarian cancer cell proliferation both in vitro and in ***,re-expression of wild-type MDH2,but not its palmitoylation-deficient C138 S mutant,sustains mitochondrial respiration and restores the growth as well as clonogenic capability of ovarian cancer ***,MDH2 palmitoylation level is elevated in clinical cancer samples from patients with high-grade serous ovarian *** observations suggest that MDH2 palmitoylation catalyzed by ZDHHC18 sustains mitochondrial respiration and promotes the malignancy of ovarian cancer,yielding possibilities of targeting ZDHHC18-mediated MDH2 palmitoylation in the treatment of EOC.

关键词： EOC MDH2 cysteine palmitoylation ZDHHC18 glutamine

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Role of cancer stem cell ecosystem on breast cancer metastasis and related mouse models

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Zoological Research 2024年第3期45卷 506-517页

作者： Xilei Peng Haonan Dong Lixing Zhang Suling Liu Fudan University Shanghai cancer Center&institutes of Biomedical Sciences/State Key Laboratory of Genetic Engineering/cancer institutes/department of oncology/Key Laboratory of Breast cancer in Shanghai/Shanghai Key Laboratory of Medical Epigenetics/Shanghai Key Laboratory of Radiation oncology/International Co-laboratory of Medical Epigenetics and Metabolism Ministry of Science and Technology/Shanghai Medical College/Fudan UniversityShanghai 200032China

Breast cancer metastasis is responsible for most breast cancer-related deaths and is influenced by many factors within the tumor ecosystem,including tumor cells and *** cancer stem cells(BCSCs)constitute a small population of cancer cells with unique characteristics,including their capacity for self-renewal and *** have shown that BCSCs not only drive tumorigenesis but also play a crucial role in promoting metastasis in breast *** tumor microenvironment(TME),composed of stromal cells,immune cells,blood vessel cells,fibroblasts,and microbes in proximity to cancer cells,is increasingly recognized for its crosstalk with BCSCs and role in BCSC survival,growth,and dissemination,thereby influencing metastatic ***,a thorough understanding of BCSCs and the TME is critical for unraveling the mechanisms underlying breast cancer *** this review,we summarize current knowledge on the roles of BCSCs and the TME in breast cancer metastasis,as well as the underlying regulatory ***,we provide an overview of relevant mouse models used to study breast cancer metastasis,as well as treatment strategies and clinical trials addressing BCSC-TME interactions during ***,this study provides valuable insights for the development of effective therapeutic strategies to reduce breast cancer metastasis.

关键词： Breast cancer Metastasis cancer stem cell Ecosystem Tumor microenvironment Mouse model

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Adjuvant chemotherapy with S-1 plus oxaliplatin improves survival of patients with gastric cancer after D2 gastrectomy: A multicenter propensity score-matched study

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World Journal of Clinical Cases 2018年第10期6卷 373-383页

作者： Deng-Feng Ren Fang-Chao Zheng Jun-Hui Zhao Guo-Shuang Shen Raees Ahmad Shui-Sheng Zhang Yu Zhang Jie Kan Li Dong Zi-Yi Wang Fu-Xing Zhao Jiu-Da Zhao department of Medical oncology Affiliated Hospital of Qinghai University Affiliated Cancer Hospital of Qinghai University department of Medical oncology Shouguang Hospital of Traditional Chinese Medicine department of Surgical oncology Affiliated Hospital of Qinghai University Affiliated Cancer Hospital of Qinghai University department of Pancreatic and Gastric Surgery National Cancer Center/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College department of Medical oncology Qinghai Red Cross Hospital department of Medical oncology People's Hospital of Qinghai Province institutes of Biomedical Sciences Shanxi University

AIM To investigate the safety and efficacy of S-1 plus oxaliplatin(SOX) as an adjuvant chemotherapy regimen in gastric cancer(GC) after D2 *** GC Patients who underwent D2 gastrectomy from September 2009 to December 2011 in four Chinese institutions were enrolled. Patients with stage ⅠB-ⅢC GC, who received adjuvant SOX treatment were matched by propensity scores with those who underwent surgery alone and those who conducted capecitabine plus oxaliplatin(XELOX) regimen. Disease-free survival(DFS) and overall survival(OS) were compared among the groups. In addition, adverse events in SOX patients were *** 1944 GC patients who underwent D2 dissection, 867 were included for analysis. One hundred and seventeen patients treated with SOX were matched to 234 patients who conducted surgery alone. Fifty-seven patients treated with SOX were matched to 57 patients who received XELOX. The estimated five-year DFS was 57.5% in the adjuvant SOX group which was higher than that(44.6%) in the surgery alone group(P = 0.001); and the estimated five-year OS was 68.3% which was higher than that(45.8%) of surgery alone group(P 60 years old subgroups(P < 0.001 and P = 0.015, respectively). Compared with XELOX regimen, SOX showed no significant difference in DFS(P = 0.340) and OS(P = 0.361). The most common ≥ 3 grade adverse events of SOX regimen were neutropenia(22.6%), leukopenia(8.9%) and thrombocytopenia(5.6%).CONCLUSION Compared with surgery alone, SOX regimen significantly improves the long-term survival and has acceptable toxicity in patients with stage ⅠB-ⅢC GC after D2 dissection. It may be a novel adjuvant chemotherapy regimen in GC patients.

关键词： Gastric cancer D2 gastrectomy Adjuvant chemotherapy S-1 Oxaliplatin Capecitabine

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Technological advances in cancer immunity:from immunogenomics to single-cell analysis and artificial intelligence

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Signal Transduction and Targeted Therapy 2021年第9期6卷 2674-2696页

作者： Ying Xu Guan-Hua Su Ding Ma Yi Xiao Zhi-Ming Shao Yi-Zhou Jiang Key Laboratory of Breast cancer in Shanghai Department of Breast SurgeryFudan University Shanghai Cancer CenterShanghaiChina department of oncology Shanghai Medical CollegeFudan UniversityShanghaiChina institutes of Biomedical Sciences Fudan UniversityShanghaiChina

Immunotherapies play critical roles in cancer ***,given that only a few patients respond to immune checkpoint blockades and other immunotherapeutic strategies,more novel technologies are needed to decipher the complicated interplay between tumor cells and the components of the tumor immune microenvironment(TIME).Tumor immunomics refers to the integrated study of the TIME using immunogenomics,immunoproteomics,immune-bioinformatics,and other multi-omics data reflecting the immune states of tumors,which has relied on the rapid development of next-generation ***-throughput genomic and transcriptomic data may be utilized for calculating the abundance of immune ceils and predicting tumor antigens,referring to ***,as bulk sequencing represents the average characteristics of a heterogeneous cell population,it fails to distinguish distinct cell ***-cell-based technologies enable better dissection of the TIME through precise immune cell subpopulation and spatial architecture *** addition,radiomics and digital pathology-based deep learning models largely contribute to research on cancer *** artificial intelligence technologies have performed well in predicting response to immunotherapy,with profound significance in cancer *** this review,we briefly summarize conventional and state-of-the-art technologies in the field of immunogenomics,single-cell and artificial intelligence,and present prospects for future research.

关键词： immuno immunity artificial

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The path forward in prostate cancer therapeutics

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Asian Journal of Andrology 2018年第3期20卷 213-214页

作者： Jeanny B Aragon-Ching Ravi A Madan department of Genitourinary Medical oncology Inova Schar Cancer Institute Fairfax VA 22031USA Genitourinary Malignancies Branch Center for Cancer Research National CancerInstitute National Institutes of Health BethesdaMD. USA

The last decade has seen remarkable advances in the treatment of prostatecancer. Until 2010, only docetaxel had demonstrated the ability to improve the survival in metastatic castration-resistant prostate cancer （mC...

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Optimal combination of antiangiogenic therapy for hepatocellular carcinoma

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World Journal of Hepatology 2015年第16期7卷 2029-2040页

作者： Hui-Ju Ch'ang National Institute of cancer Research National Health Research Institutes department of Radiation oncology Taipei Medical University Hospital

The success of sorafenib in prolonging survival of patients with hepatocellular carcinoma(HCC) makes therapeutic inhibition of angiogenesis a component of treatment for HCC. To enhance therapeutic efficacy, overcomedrug resistance and reduce toxicity, combination of antiangiogenic agents with chemotherapy, radiotherapy or other targeted agents were evaluated. Nevertheless, the use of antiangiogenic therapy remains suboptimal regarding dosage, schedule and duration of therapy. The issue is further complicated by combination antiangiogenesis to other cytotoxic or biologic agents. There is no way to determine which patients are most likely respond to a given form of antiangiogenic therapy. Activation of alternative pathways associated with disease progression in patients undergoing antiangiogenic therapy has also been recognized. There is increasing importance in identifying, validating and standardizing potential response biomarkers for antiangiogenesis therapy for HCC patients. In this review, biomarkers for antiangiogenesis therapy including systemic, circulating, tissue and imaging ones are summarized. The strength and deficit of circulating and imaging biomarkers were further demonstrated by a series of studies in HCC patients receiving radiotherapy with or without thalidomide.

关键词： Antiangiogenesis Hepatocellular carcinoma Biomarker Cytokines Dynamic contrast enhancedmagnetic resonance imaging

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