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prostate specific membrane antigen knockdown impairs the tumorigenicity of LNCaP prostate cancer cells by inhibiting the phosphatidylinositol 3-kinase/Akt signaling pathway

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中华医学杂志(英文版) 2014年第5期127卷 924-931页

作者： Guo Zhenghui Lai Yiming Du Tao Zhang Yiming Chen Jieqing Bi Liangkuan Lin Tianxin Liu Hao Wang Wei Xu Kewei Jiang Chun Han Jinli Zhang Caixia Dong Wen Huang Jian Huang Hai Department of Urology Sun Yat-sen Memorial Hospital Sun Yatsen University Prenatal Diagnosis Center Sun Yat-sen Memorial Hospital Sun Yatsen University Department of Urology General Hospital of Guangzhou Military Command of People’s Liberation Army

Background prostate specific membrane antigen(PSMA)can facilitate the growth,migration,and invasion of the LNCaP prostate cancer cell lines,but the underlying molecular mechanisms have not yet been clearly defined.Here,we investigated whether PSMA serves as a novel regulator of the phosphatidylinositol 3-kinase(PI3K)/Akt signaling by employing PSMA knockdown model and PI3K pharmacological inhibitor(LY294002)in LNCaP prostate cancer cells.Methods PSMA knockdown had been stably established by transfecting with lentivirus-mediated siRNA in our previous study.Then,LNCaP cells were divided into interference,non-interference,and blank groups.We first testified the efficacy of PSMA knockdown in our LNCaP cell line.Then,we compared the expression of PSMA and total/activated Akt by Western blotting in the above three groups with or without LY294002 treatment.Furthermore,immunocytochemistry was performed to confirm the changes of activated Akt(p-Akt,Ser473)in groups.Besides,cell proliferation,migration,and cell cycle were measured by CCK-8 assay,Transwell analysis,and Flow cytometry respectively.Results After PSMA knockdown,the level of p-Akt(Ser473)but not of total-Akt(Akt1/2)was significantly decreased when compared with the non-interference and blank groups.However,LY294002 administration significantly reduced the expression of p-Akt(Ser473)in all the three groups.The results of immunocytochemistry further confirmed that PSMA knockdown or LY294002 treatment was associated with p-Akt(Ser473)down-regulation.Decrease of cell proliferation,migration,and survival were also observed upon PSMA knockdown and LY294002 treatment.Conclusions Taken together,our results reveal that PI3K/Akt signaling pathway inhibition may serve as a novel molecular mechanism in LNCaP prostate cancer cells of PSMA knockdown and suggest that Akt(Ser473)may play a critical role as a downstream signaling target effector of PSMA in this cellular model.

关键词： prostate cancer LNCaP cells prostate-specific membrane antigen RNA interference PI3K/Akt pathway tumorigenicity

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prostate-specific membrane antigen expression in hepatocellular carcinoma,cholangiocarcinoma,and liver cirrhosis

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World Journal of Gastroenterology 2020年第48期26卷 7664-7678页

作者： Li-Xing Chen Si-Juan Zou Dan Li Jian-Yuan Zhou Zhao-Ting Cheng Jun Zhao Yuan-Li Zhu Dong Kuang Xiao-Hua Zhu Department of Nuclear Medicine Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030Hubei ProvinceChina School of Basic Medicine Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030Hubei ProvinceChina Department of Pathology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030Hubei ProvinceChina

BACKGROUND Primary liver cancer includes three subtypes:Hepatocellular carcinoma(HCC),intrahepatic cholangiocarcinoma(CCA),and combined hepatocellular carcinoma.Patients with primary liver cancer experienced poor prognosis and high mortality,so early detection of liver cancer and improved management of metastases are both key strategies to reduce the death toll from liver cancer.prostate-specific membrane antigen(PSMA)expression in the tumor-associated neovasculature of nonprostate malignancies including liver cancer has been reported recently,but conclusive evidence of PSMA expression based on the pathological type of liver cancer remains limited.AIM To study the expression of PSMA in HCC,CCA,and liver cirrhosis.METHODS A total of 446 formalin-fixed paraffin-embedded(FFPE)liver tumor and liver cirrhosis tissue samples were obtained retrospectively from the Pathology Department of Tongji Hospital.Immunohistochemistry was used to detect PSMA expression in these 446 FFPE liver biopsy specimens(213 HCC,203 CCA,and 30 liver cirrhosis).The tumor compartment and the associated neovascular endothelium were separately analyzed.PSMA expression was examined by two certified pathologists,and the final results were presented in a 4-point scoring system(0-3 points).Correlation between PSMA expression and clinicopathological information was also assessed.RESULTS PSMA was expressed primarily in the neovascular endothelium associated with tumors.The positive rate of PSMA staining in HCC was significantly higher than that in CCA(86.8%vs 79.3%;P=0.001)but was only 6.6%in liver cirrhosis(P=0.000).HCC cases had more 3-score PSMA staining than CCA had(89/213,41.8%vs 35/203,17.2%;P=0.001).PSMA expression correlated positively with the stage and grade of HCC and CCA.In both liver cancer subtypes,there were more PSMA+cases in stages III–V diseases than in stages I and II.High staining intensity of PSMA was more frequently observed in liver cancers at high grade and advanced stage.There was no significant association of PSMA expression w

关键词： prostate-specific membrane antigen Hepatocellular carcinoma Cholangiocarcinoma Liver cirrhosis Neovasculature Immunohistochemistry

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New frontiers in focal therapy for prostate cancer:prostate-specific membrane antigen positron emission tomography/magnetic resonance imaging

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World Journal of Clinical Oncology 2021年第2期12卷 61-68页

作者： Celeste Manfredi Esau Fernandez-Pascual Estefanía Linares-Espinós Felipe Couñago Juan Ignacio Martínez-Salamanca Department of Woman Child and General and Specialized SurgeryUrology UnitUniversity of Campania“Luigi Vanvitelli”Naples 81110Italy Department of Urology Hospital Universitario La PazMadrid 28046Spain LYX Institute of Urology Facultad de MedicinaUniversidad Francisco de VitoriaPozuelo de Alarcón 28223MadridSpain Radiation Oncology Hospital Universitario Quirónsalud MadridPozuelo de Alarcón 28223MadridSpain Department of Urology Hospital Universitario Puerta Hierro-MajadahondaMajadahonda 28222MadridSpain

Imaging has a central role in the context of focal therapy(FT)for prostate cancer(PCa).prostate-specific membrane antigen(PSMA)positron emission tomography/magnetic resonance imaging(PET/MRI)is a novel imaging modality that combines the morpho-functional information of MRI with the molecular characterization of PET.Some papers reported the potential advantages of PSMA PET/MRI in different clinical scenarios.Limited evidence on PSMA PET/MRI is available in the setting of FT.PSMA PET/MRI can be an effective imaging modality for detecting primary PCa and seems to provide accurate local staging of primary PCa.PSMA PET/MRI also shows high performance for restaging and detecting tumor recurrence.The higher soft-tissue contrast and the reduction of ionizing radiation are the main advantages reported in the literature compared to PET/computed tomography.PSMA PET/MRI could represent a turning point in the management of patients with PCa in the context of FT.Further studies are needed to confirm its applications in this specific clinical setting.

关键词： prostate-specific membrane antigen Positron emission tomography/magnetic resonance imaging prostate cancer Focal therapy High-intensity focused ultrasound Cryotherapy

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Evaluation of the reducing potential of PSMA-containing endosomes by FRET imaging

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Cancer Drug Resistance 2021年第1期4卷 223-232页

作者： Chelvam Venkatesh Jiayin Shen Karson S.Putt Philip S.Low Discipline of Chemistry Indian Institute of TechnologyMadhya PradeshIndore 453552India Discipline of Bioscience and Biomedical Engineering Indian Institute of TechnologyMadhya PradeshIndore 453552India Department of Chemistry Purdue UniversityWest LafayetteIN 47907USA Institute for Drug Discovery Purdue UniversityWest LafayetteIN 47907USA

Aim:Ligand-targeted therapeutics are experiencing increasing use for treatment of human diseases due to their ability to concentrate a desired drug at a pathologic site while reducing accumulation in healthy tissues.For many ligand-targeted drug conjugates,a critical aspect of conjugate design lies in engineering release of the therapeutic payload to occur only after its internalization by targeted cells.Because disulfide bond reduction is frequently exploited to ensure intracellular drug release,an understanding of the redox properties of endocytic compartments can be critical to ligand-targeted drug design.While the redox properties of folate receptor trafficking endosomes have been previously reported,little is known about the trafficking of prostate-specific membrane antigen(PSMA),a receptor that is experiencing increasing use for drug targeting in humans.Methods:To obtain this information,we have constructed a PSMA-targeted fluorescence resonance energy transfer pair that reports on disulfide bond reduction by changing fluorescence from red to green.Results:We show here that this reporter exhibits rapid and selective uptake by PSMA-positive cells,and that reduction of its disulfide bond proceeds steadily but incompletely following internalization.The fact that maximal disulfide reduction reaches only~50%,even after 24 h incubation,suggests that roughly half of the conjugates must traffic through endosomes that display no reducing capacity.Conclusion:As the level of disulfide reduction differs between PSMA trafficked and previously published folate trafficked conjugates,it also follows that not all internalizing receptors are translocated through similar intracellular compartments.Taken together,these data suggest that the efficiency of disulfide bond reduction must be independently analyzed for each receptor trafficking pathway when disulfide bond reduction is exploited for intracellular drug release.

关键词： DUPA prostate-specific membrane antigen endosomes endocytosis

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Development of PSMA-targeted and core-crosslinked glycol chitosan micelles for docetaxel delivery in prostate cancer therapy

Development of PSMA-targeted and core-crosslinked glycol chi...

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2018年第十二届中国药物制剂大会

作者： Xiang Feng Yunfeng Zhou Xin Xie Ming Li Hao Huang Liangliang Wang Xiao Xu 余敬谋 School of Pharmacy and Life Sciences Jiujiang University School of Chemical and Biological Engneering Yichun University Key Laboratory of Jiangxi Province for Systems Biomedicine Jiujiang University Affiliated Hospital of Jiujiang University

In this study, prostate-specific membrane antigen（PSMA）-targeted and core-crosslinked micelles were developed based on prostate cancer-binding peptide（PCP） modified glycol chitosan-lipoic acid（PGCLA） conjugate. The degree of substitution was 5.2 PCP groups and 10.7 lipoic acid groups per 100 sugar residues of glycol chitosan in PGC-LA copolymer. Docetaxel（DTX） was chosen as a model anti-tumor drug. The DTX-loaded micelles were prepared by an o/w method, and core-crosslinked micelles were further constructed by using a catalytic amount of dithiothreitol. The mean diameter of DTX-loaded core-crosslinked PGC-LA（DTX-PGC-LA/cc） micelles was 397 nm determined by dynamic light scattering（DLS）. In vitro DTX released from core-crosslinked micelles was slower than that from non-crosslinked counterpart. Blank micelles exhibited good biocompatibility. Additionally, cellular uptake and cytotoxcity of PCP-modified micelles were higher than those of micelles without PCP in PSMA-positive LNCaP cells. Importantly, DTXPGC-LA/cc demonstrated the stronger anti-tumor efficacy against LNCaP tumor xenograft models than DTX injection and other DTX-loaded micelles. Taken together, this study provides a potential way in developing actively targeted and core-crosslinked micelles for hydrophobic drug delivery in cancer therapy.

关键词： Core-crosslink Targeted micelles prostate-specific membrane antigen Glycol chitosan Docetaxel

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