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NEDD8-conjugating enzyme UBC12 as a novel therapeutic target in esophageal squamous cell carcinoma

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Signal Transduction and Targeted Therapy 2020年第1期5卷 1403-1406页

作者： Shiwen Wang Jingrong Xian Lihui Li Yanyu Jiang Yue Liu Lili Cai robert m.hoffman Lijun Jia Hu Zhao Yanmei Zhang Department of Laboratory medicine Huadong Hospital Affiliated to Fudan UniversityShanghai 200040China Cancer Institute Longhua HospitalShanghai University of Traditional Chinese MedicineShanghai 200032China Research Center on Aging and medicine Fudan UniversityShanghai 200040China Shanghai Key Laboratory of Clinical Geriatric medicine Shanghai 200040China Department of Surgery University of CaliforniaSan DiegoCAUSA

Dear Editor,Esophageal squamous cell carcinoma(ESCC)is the major histologic subtype of esophageal cancer with high incidence and mortality.1 However,few achievements have been made in the development of targeted drugs.2 Neddylation,a reversible post-translational modification,attaches ubiquitin-like molecule NEDD8 to substrates in a three-step enzymatic reaction catalyzed by NEDD8-activating enzyme E1(NAE,NAE1 and UBA3 heterodimer),NEDD8-conjugating enzyme E2s(UBE2m/UBC12 or UBE2F)and substrate-specific NEDD8-E3 ligases.3 The best-characterized substrates of neddylation are cullin family proteins,the essential components of multiunit Cullin-RING ubiquitin ligases(CRLs).4 Currently,the inhibition of cullin neddylation by targeting overactivated neddylation pathway has emerged as an attractive approach for anticancer therapy.5,6 Our previous study reported that mLN4924,a specific inhibitor of NAE,significantly inhibited the tumor growth of ESCC by blocking cullin neddylation and inactivating CRLs activity.7 However,recent studies found that mLN4924 treatment-emergent NAE mutations would confer the drug resistance.8,9 Therefore,it is urgent to identify other neddylation enzymes(E2s or E3s)as alternative anticancer targets and develop novel anti-ESCC strategies.

关键词： esophageal NEDD8 squamous

Inhibition of growth and metastasis of triple-negative breast cancer targeted by Traditional Chinese medicine Tubeimu in orthotopic mice models

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Chinese Journal of Cancer Research 2018年第1期30卷 112-121页

作者： Jingxiao Wang Xinjie Yang Haibo Han Limin Wang Weiqian Bao Shanshan Wang robert m.hoffman meng Yang Hui Qi Chao An Kaiwen Hu Beijing University of Chinese medicine Beijing 100029 China Key Laboratory of Carcinogenesis and Translational Research (ministry of Education/Beijing) Department of Biobank Peking University Cancer Hospital & Institute Beijing 100142 China Anti Cancer Inc. San DiegoCA 92111 USA Department of Surgery University of California San Diego CA 92103-8220 USA Anti Cancer Biotech Co Ltd. Beijing102200 China Department of Oneology Dongfang Hospital Beijing University of Chinese Medicine Beijing 100078 China

Objective： Triple-negative breast cancer（TNBC） is highly invasive and metastatic, which is in urgent need of transformative therapeutics. Tubeimu（TBm）, the rhizome of Bolbostemma paniculatum（maxim.） Franquet, is one of the Chinese medicinal herbs used for breast diseases since the ancient times. The present study evaluated the efficacy, especially the anti-metastatic effects of the dichloromethane extract of Tubeimu（ETBm） on TNBC orthotopic mouse models and cell ***： We applied real-time imaging on florescent orthotopic TNBC mice model and tested cell migration and invasion abilities with mDA-mB-231 cell line. Digital gene expression sequencing was performed and Kyoto Encyclopedia of Genes and Genomes（KEGG） analysis applied to explore the pathways influenced by ***, quantitative real-time polymerase chain reactions（q RT-PCR） and Western blot were delivered to confirm the gene expression ***： ETBm exhibited noticeable control on tumor metastasis and growth of TNBC tumors with no obvious toxicity. In compliance with this, it also showed inhibition of cell migration and invasion in vitro. Its impact on the changed biological behavior in TNBC may be a result of decreased expression of integrin β1（ITGβ1）, integrin β8（ITGβ8） and Rho GTPase activating protein 5（ARHGAP5）, which disabled the focal adhesion pathway and caused change in cell ***： This study reveals that ETBm has anti-metastatic effects on mDA-mB-231-GFP tumor and may lead to a new therapeutic agent for the integrative treatment of highly invasive TNBC.

关键词： Tubeimu triple negative breast cancer(TNBC) orthotopic mouse models Traditional Chinese medicine(TCm) integrins Rho GTPase activating protein 5

Pro-senescence neddylation inhibitor combined with a senescence activated β-galactosidase prodrug to selectively target cancer cells

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Signal Transduction and Targeted Therapy 2022年第10期7卷 3645-3648页

作者： Shuaishuai Ni Qian Liu Xin Chen Lele Ding Lili Cai Fei mao Donglei Shi robert m.hoffman Jian Li Lijun Jia Cancer Institute Longhua HospitalShanghai University of Traditional Chinese Medicine200032 ShanghaiChina State Key Laboratory of Bioreactor Engineering Shanghai Frontiers Science Center of Optogenetic Techniques for Cell MetabolismFrontiers Science Center for Materiobiology and Dynamic ChemistryShanghai Key Laboratory of New Drug DesignSchool of PharmacyEast China University of Science and Technology200037 ShanghaiChina Department of Surgery University of CaliforniaSan DiegoCAUSA

Dear Editor,Targeting senescence therapy is a promising anticancer strategy by arresting the cell-cycle and inducing cellular ***,senescent cells can promote malignancy and drug resistance.1,2 Thus,with the induction of senescence emerged as a viable therapeutic concept,it is important to consider how to eliminate those senescent cancer cells.

关键词： viable cancer eliminate

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中药土贝母诱导人乳腺癌细胞凋亡的实时成像

中华中医药杂志 2012年第7期27卷 1810-1814页

作者：胡明昕安超李泉旺 robert m.hoffman 赵明杨萌傅延龄倪胜楼胡凯文北京中医药大学东方医院北京100078 北京中医药大学东方医院肿瘤科北京100078 美国安泰康生物技术有限公司美国圣地亚哥92111 美国加州大学外科系美国圣地亚哥92103 北京中医药大学国际学院北京100029

目的:采用先进的荧光实时显像技术对中药土贝母植物块茎提取物抗乳腺癌作用进行评价。方法:mDA-mB-231人乳腺癌细胞被设计成为细胞质红色荧光蛋白(RFP)基因表达而细胞核组蛋白H2B绿色荧光蛋白(GFP)基因表达的双色荧光细胞,并分别在2D平... 详细信息

目的:采用先进的荧光实时显像技术对中药土贝母植物块茎提取物抗乳腺癌作用进行评价。方法:mDA-mB-231人乳腺癌细胞被设计成为细胞质红色荧光蛋白(RFP)基因表达而细胞核组蛋白H2B绿色荧光蛋白(GFP)基因表达的双色荧光细胞,并分别在2D平面塑料平皿及3D立体明胶海绵块两种不同的培养环境中培养,经土贝母鲜品二氯甲烷提取物(DEFT)干预后,荧光共聚焦显微镜下观察细胞形态及核碎片形成的情况;DNA电泳方法进一步检测细胞凋亡。结果:土贝母鲜品二氯甲烷提取物作用24h后荧光显微镜下即观察到mDA-mB-231细胞出现凋亡的形态学改变;DNA电泳在药物干预48h后检测到凋亡的DNA碎片梯带,72h后更加明显;3D明胶海绵培养的mDA-mB-231细胞经实验药物作用后其形态学改变的效果不如2D环境下明显。结论:土贝母鲜品二氯甲烷提取成分具有抗乳腺癌治疗的潜能。

关键词：土贝母鲜品二氯甲烷提取物双色荧光蛋白双色人乳腺癌细胞mDA-mB-231 实时荧光显微成像明胶海绵3D培养 DNA电泳凋亡

土贝母提取物对人乳腺癌mDA-mB-231-GFP裸鼠模型的抗肿瘤作用评价

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中华中医药杂志 2013年第2期28卷 390-393,I0001页

作者：安超杨萌胡明昕傅延龄李泉旺曹阳 robert m.hoffman 齐慧刘永刚胡凯文北京中医药大学东方医院北京100078 安泰康生物技术(北京)有限公司北京102200 北京中医药大学北京100029

目的:建立绿色荧光蛋白标记的人乳腺癌mDA-mB-231-GFP裸鼠模型,研究中药土贝母提取物对转染GFP基因的人乳腺癌mDA-mB-231-GFP裸鼠模型的抗肿瘤活性。方法:应用原位移植方法,建立绿色荧光蛋白标记的人乳腺癌mDA-mB-231-GFP模型。通过比... 详细信息

目的:建立绿色荧光蛋白标记的人乳腺癌mDA-mB-231-GFP裸鼠模型,研究中药土贝母提取物对转染GFP基因的人乳腺癌mDA-mB-231-GFP裸鼠模型的抗肿瘤活性。方法:应用原位移植方法,建立绿色荧光蛋白标记的人乳腺癌mDA-mB-231-GFP模型。通过比较阴性对照组(口服0.9%氯化钠溶液)、阳性对照组(腹腔注射紫衫醇20mg/kg)、低剂量组(口服土贝母提取物10mg/kg)和高剂量组(口服土贝母提取物50mg/kg)的肿瘤抑制率,评价土贝母提取物对肿瘤生长的影响。结果:阴性对照组与各治疗组小鼠给药前后体质量变化比较,差异均无统计学意义,一般状况良好。低剂量组和阴性对照组间比较,肿瘤大小和体质量的改变差异无统计学意义;高剂量组和阳性对照组肿瘤较阴性对照组明显缩小(PmDA-mB-231-GFP裸鼠模型有明显的抑制作用。

关键词：土贝母提取物乳腺癌人乳腺癌mDA-mB-231-GFP裸鼠模型抗肿瘤活性

Overexpressed NEDD8 as a potential therapeutic target in esophageal squamous cell carcinoma

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Cancer Biology & medicine 2022年第4期19卷 504-517页

作者： Jingrong Xian Shiwen Wang Yanyu Jiang Lihui Li Lili Cai Ping Chen Yue Liu Xiaofei Zeng Guoan Chen Chen Ding robert mhoffman Lijun Jia Hu Zhao Yanmei Zhang Department of Laboratory medicine Huadong Hospital Affiliated to Fudan UniversityShanghai 200040China Cancer Institute Longhua HospitalShanghai University of Traditional Chinese MedicineShanghai 200032China Research Center on Aging and medicine Fudan UniversityShanghai 200040China Shanghai Key Laboratory of Clinical Geriatric medicine Shanghai 200040China Department of Basic Science of Oncology College of Basic Medical SciencesZhengzhou UniversityCollaborative Innovation Center of Henan Province for Cancer ChemopreventionZhengzhou 450001China School of medicine Southern University of Science and TechnologyShenzhen 518055China State Key Laboratory of Genetic Engineering Human Phenome InstituteInstitutes of Biomedical SciencesSchool of Life SciencesZhongshan HospitalFudan UniversityShanghai 200032China State Key Laboratory of Cell Differentiation and Regulation Henan International Joint Laboratory of Pulmonary FibrosisHenan Center for Outstanding Overseas Scientists of Pulmonary FibrosisCollege of Life ScienceInstitute of Biomedical ScienceHenan Normal UniversityXinxiang 453007China Department of Surgery University of CaliforniaSan Diego 92101USA Anticancer Inc. San Diego 92101USA

Objective:The hyperactivated neddylation pathway plays an important role in tumorigenesis and is emerging as a promising anticancer *** aimed to study whether NEDD8(neural precursor cell expressed,developmentally down-regulated 8)might serve as a therapeutic target in esophageal squamous cell carcinoma(ESCC).methods:The clinical relevance of NEDD8 expression was evaluated by using The Cancer Genome Atlas(TCGA)database and tissue ***8-knockdown ESCC cells generated with the CRISPR/Cas9 system were used to explore the anticancer effects and *** proteomic analysis was used to examine the variations in NEDD8 knockdown-induced biological *** cell cycle and apoptosis were assessed with fluorescence activated cell sorting.A subcutaneous-transplantation mouse tumor model was established to investigate the anticancer potential of NEDD8 silencing in ***:NEDD8 was upregulated at both the mRNA and protein expression levels in ESCC,and NEDD8 overexpression was associated with poorer overall patient survival(mRNA level:P=0.028,protein level:P=0.026,log-rank test).Downregulation of NEDD8 significantly suppressed tumor growth both in vitro and in *** proteomic analysis revealed that downregulation of NEDD8 induced cell cycle arrest,DNA damage,and apoptosis in ESCC *** studies demonstrated that NEDD8 knockdown led to the accumulation of cullin-RING E3 ubiquitin ligases(CRLs)substrates through inactivation of CRLs,thus suppressing the malignant phenotype by inducing cell cycle arrest and apoptosis in *** experiments demonstrated that the induction of apoptosis after NEDD8 silencing was attenuated by DR5 ***:Our study elucidated the anti-ESCC effects and underlying mechanisms of NEDD8 knockdown,and validated NEDD8 as a potential target for ESCC therapy.

关键词： NEDD8 esophageal squamous cell carcinoma cullin-RING E3 ubiquitin ligases apoptosis anticancer target

鲜土贝母二氯甲烷提取物对人乳腺癌mDA-mB-231-GFP裸鼠肿瘤生长及肺转移的抑制作用

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中医药导报 2017年第23期23卷 18-21,34页

作者：鲍伟倩王婧筱安超胡凯文杨萌 robert m.hoffman 齐慧曹阳北京中医药大学东方医院北京100078 安泰康生物技术(北京)有限公司北京102200 美国加州大学外科系美国圣地亚哥92103

目的:研究土贝母鲜品二氯甲烷提取物(DEFT)对绿色荧光蛋白标记的人三阴性乳腺癌mDA-mB-231-GFP裸鼠模型中移植瘤生长和肺转移的作用。方法:应用外科原位移植方法,建立人乳腺癌裸鼠移植模型,随机分成3组,阴性对照组(0.9%Na Cl)、低剂量组... 详细信息

目的:研究土贝母鲜品二氯甲烷提取物(DEFT)对绿色荧光蛋白标记的人三阴性乳腺癌mDA-mB-231-GFP裸鼠模型中移植瘤生长和肺转移的作用。方法:应用外科原位移植方法,建立人乳腺癌裸鼠移植模型,随机分成3组,阴性对照组(0.9%Na Cl)、低剂量组(DEFT 50 mg/kg)和高剂量组(DEFT 75 mg/kg),每组5只,灌胃给药,1次/d,连续58 d。每周2次荧光成像系统釆集肿瘤图像,系统自带软件计算肿瘤面积;给药结束时,称取肿瘤质量,荧光成像系统观察肺转移情况。结果:给药前后3组裸鼠体质量变化差异均无统计学意义(P>0.05)。给药第14天,3组肿瘤面积比较,差异有统计学意义(P0.05)。结论:鲜土贝母二氯甲烷提取物对人三阴性乳腺癌mDA-mB-231-GFP裸鼠模型中肿瘤生长及肺转移的发生有一定抑制作用。

关键词：土贝母提取物中药提取物乳腺癌人乳腺癌mDA-mB-231-GFP祼鼠模型肺转移

Patient-derived orthotopic xenograft models for cancer of unknown primary precisely distinguish chemotherapy,and tumor-targeting *** A1-R is superior to first-line chemotherapy

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Signal Transduction and Targeted Therapy 2018年第1期3卷 220-225页

作者： Kentaro miyake Tasuku Kiyuna masuyo miyake Kei Kawaguchi Sang Nam Yoon Zhiying Zhang Kentaro Igarashi Sahar Razmjooei Sintawat Wangsiricharoen Takashi murakami Yunfeng Li Scott D.Nelson Tara A.Russell Arun S.Singh Yukihiko Hiroshima masashi momiyama Ryusei matsuyama Takashi Chishima Shree Ram Singh Itaru Endo Fritz C.Eilber robert m.hoffman AntiCancer Inc.San DiegoCAUSA Department of Surgery University of CaliforniaSan DiegoCAUSA Department of Gastroenterological Surgery Yokohama City University Graduate School of MedicineYokohamaJapan Department of Pathology University of CaliforniaLos AngelesCAUSA Division of Surgical Oncology University of CaliforniaLos AngelesCAUSA Division of Hematology-Oncology University of CaliforniaLos AngelesCAUSA Basic Research Laboratory National Cancer InstituteFrederickMDUSA

Cancer of unknown primary(CUP)is a recalcitrant disease with poor prognosis because it lacks standard first-line *** consists of diverse malignancy groups,making personalized precision therapy *** present study aimed to identify an effective therapy for a CUP patient using a patient-derived orthotopic xenograft(PDOX)*** paper reports the usefulness of the PDOX model to precisely identify effective and ineffective chemotherapy and to compare the efficacy of *** A1-R with first-line chemotherapy using the CUP PDOX *** present study is the first to use a CUP PDOX model,which was able to precisely distinguish the chemotherapeutic *** found that a carboplatinum(CAR)-based regimen was effective for this CUP *** also demonstrated that *** A1-R was more effective against the CUP tumor than first-line *** results indicate that *** A1-R has clinical potential for CUP,a resistant disease that requires effective therapy.

关键词： chemotherapy precisely therapy

Protein neddylation pathway is overactivated and serves as an attractive target in human lung cancer

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Protein neddylation pathway is overactivated and serves as a...