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Glycolytic potential enhanced by blockade of pyruvate influx into mitochondria sensitizes prostate cancer to detection and radiotherapy

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cancer Biology & Medicine 2022年第9期19卷 1315-1333页

作者： Huan Xu Junyi Chen Zhi Cao Xi Chen Caihong Huang Jin Ji Yalong Xu Junfeng Jiang Yue Wang Guowang Xu Lina Zhou Jingyi He Xuedong Wei Jason Boyang Wu Zhong Wang Shancheng Ren Fubo Wang Department of Urology Shanghai Changhai HospitalSecond Military Medical UniversityShanghai 200433China Department of Urology Shanghai Ninth People’s HospitalShanghai 200011China Department of Urology the Second Affiliated Hospital of Fujian Medical UniversityQuanzhou 362000China Department of Urology No.971 Hospital of the People’s Liberation Army NavyQingdao 266000China Center for Genomic and Personalized Medicine Guangxi Key Laboratory for Genomic and Personalized MedicineGuangxi Collaborative Innovation Center for Genomic and Personalized MedicineGuangxi Medical UniversityNanning 530021China Research Center of Developmental Biology Second Military Medical UniversityShanghai 200433China Dalian Institute of Chemical Physics Chinese Academy of SciencesDalian 116023China Department of Urology the First Affiliated Hospital of Soochow UniversitySuzhou 215006China Department of Pharmaceutical Sciences College of Pharmacy and Pharmaceutical SciencesWashington State UniversitySpokaneWA 99202USA

Objective:This study aimed to evaluate the effects of mitochondrial pyruvate carrier(MPC)blockade on the sensitivity of detection and radiotherapy of prostate cancer(PCa).Methods:We investigated glycolysis reprogramming and MPC changes in patients with PCa by using metabolic profiling,RNASeq,and tissue *** blockade of pyruvate influx into mitochondria was observed in cellular studies to detect its different effects on prostate carcinoma cells and benign prostate *** mouse models were injected with an MPC inhibitor to evaluate the sensitivity of 18F-fluorodeoxyglucose positron emission tomography with computed tomography and radiotherapy of ***,the molecular mechanism of this different effect of transient blockage towards benign prostate cells and prostate cancer cells was studied in ***:MPC was elevated in PCa tissue compared with benign prostate tissue,but decreased during cancer *** transient blockade increased PCa cell proliferation while decreasing benign prostate cell proliferation,thus increasing the sensitivity of PCa cells to 18F-PET/CT(SUVavg,P=0.016;SUVmax,P=0.03)and radiotherapy(Pprostate cells was dependent on regulation by a VDAC1-MPC-mitochondrial homeostasis-glycolysis ***:Blockade of pyruvate influx into mitochondria increased glycolysis levels in PCa but not in non-carcinoma prostate *** transient blockage sensitized PCa to both detection and radiotherapy,thus indicating that glycolytic potential is a novel mechanism underlying PCa *** change in the mitochondrial pyruvate influx caused by transient MPC blockade provides a critical target for PCa diagnosis and treatment.

关键词： Glycolytic potential prostate cancer mitochondrial pyruvate carrier(MPC) mitochondria pyruvate influx diagnosis radiotherapy

Photoacoustic imaging of prostate cancer

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Journal of Innovative Optical Health Sciences 2017年第4期10卷 70-83页

作者： Xuanjin Yang Liangzhong Xiang Stephenson Research and Technology Center University of Oklahoma Norman Oklahoma 73019USA School of Electrical and Computer Engineering University of Oklahoma Norman Oklahoma 73019 USA

Photoacoustic imaging(PAI),also known as optoacoustic imaging,is a rapidly growing imaging modality with potential in medical diagnosis and therapy *** paper focuses on the techniques of prostate PAI and its potential applications in prostate cancer *** light delivery combined with transrectal ultrasound detection overcomes light scattering in the surrounding tissue and provides optimal photoacoustic signals while minimizing *** label-free PAI based on endogenous contrast has promising potential for prostate cancer detection,exogenous contrast agents can further enhance the sensitivity and speci¯city of prostate cancer *** in vivo studies are required in order to achieve the translation of prostate PAI to clinical *** minimal invasiveness,relatively low cost,high speci¯city and sensitivity,and real-time imaging capability are valuable advantages of PAI that may improve the current prostate cancer management in clinic.

关键词： Photoacoustic/optoacoustic imaging prostate cancer cancer therapy monitoring prostate endoscopy cellular imaging.

Evaluation of PSA-age volume score in predicting prostate cancer in Chinese population

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Asian Journal of Andrology 2018年第4期20卷 324-329页

作者： Yi-Shuo Wu Xiao-Bo Wu Ning Zhang Guang-Liang Jiang Yang Yu Shi-Jun Tong Hao-Wen Jiang Shan-Hua Mao Rong Na Qiang Ding Department of Urology Huashan Hospital Fudan University Shanghai 200040 China Urology Research Center Fudan University Shanghai 200040 China Department of Urology Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200025 China

This study was performed to evaluate prostate-specific antigen-age volume （PSA-AV） scores in predicting prostate cancer （PCa） in a Chinese biopsy population. A total of 2355 men who underwent initial prostate biopsy from January 2006 to November 2015 in Huashan Hospital were recruited in the current study. The PSA-AV scores were calculated and assessed together with PSA and PSA density （PSAD） retrospectively. Among 2133 patients included in the analysis, 947 （44.4%） were diagnosed with PCa. The mean age, PSA, and positive rates of digital rectal examination result and transrectal ultrasound result were statistically higher in men diagnosed with PCa （all P 〈 0.05）. The values of area under the receiver operating characteristic curves （AUCs） of PSAD and PSA-AV were 0.864 and 0.851, respectively, in predicting PCa in the entire population, both performed better than PSA （AUC = 0.805; P 〈 0.05）. The superiority of PSAD and PSA-AV was more obvious in subgroup with PSA ranging from 2.0 ng ml^-1 to 20.0 ng ml^-1. A PSA-AV score of 400 had a sensitivity and specificity of 93.7% and 40.0%, respectively. In conclusion, the PSA-AV score performed equally with PSAD and was better than PSA in predicting PCa. This indicated that PSA-AV score could be a useful tool for predicting PCa in Chinese population.

关键词： age China prostate cancer prostate-specific antigen volume

Environmental Exposure to Lead as a Risk for prostate cancer

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Biomedical and Environmental Sciences 2002年第4期15卷 298-305页

作者： M．K．J．SIDDIQUI S．SRIVASTAVA 等 IndustialToxicologyReserachCentre PostBoxNo.80.M.G.Marg.Lucknow226－001India Dr RMLAvadhUniversityFaizabad－224001India

Objective To evaluate the possible role of environmental exposure to lead as a risk factor for prostate pathology in patients suffering from prostate cancer (PCA) and benign prostate hyperplasia (BPH). Methods Blood lead (BPb) level was determined in PCA and BPH cases using a graphite furnace Atomic Absorption Spectrophotometer and compared with those in a control group living in the similar socioeconomic environment. Results BPb was significantly higher in PCA and BPH cases than in normals (Pprostate cancer and/or benign prostate hyperplasia possibly through generation of reactive oxygen species and/or reducing the level of zinc which acts as a cellular growth protector.

关键词： Benign prostate hyperplasia prostate cancer Blood lead Atomic Absorption Spectrophotometer

Redox responsive polymeric nanoparticles enhance the efficacy of cyclin dependent kinase 7 inhibitor for enhanced treatment of prostate cancer

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Chinese Chemical Letters 2024年第8期35卷 443-448页

作者： Yiran Tao Chunlei Dai Zhaoxiang Xie Xinru You Kaiwen Li Jun Wu Hai Huang Department of Urology Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China Department of Urology The Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhou 510120China Biomedical Innovation Center The Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhou 510120China School of Biomedical Engineering Sun Yat-sen UniversityShenzhen 518107China Center for Nanomedicine and Department of Anesthesiology Brigham and Women’s HospitalHarvard Medical SchoolBostonMA 02115United States Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Sun Yat-sen Memorial HospitalSun Yat-Sen UniversityGuangzhou 510120China Department of Urology The Sixth Affiliated Hospital of Guangzhou Medical UniversityQingyuan People’s HospitalQingyuan 511518China Bioscience and Biomedical Engineering Thrust The Hong Kong University of Science and Technology(Guangzhou)Guangzhou 511400China Division of Life Science The Hong Kong University of Science and TechnologyHong KongChina Guangdong Provincial Clinical Research Center for Urological Diseases Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510120China

Traditional therapies such as surgery and endocrine therapy no longer meet the clinical needs in prostate cancer treatment,and more effective treatments are urgently *** studies have reported that targeted inhibition of the transcription factor cyclin dependent kinase 7(CDK7)could effectively suppress prostate cancer ***,the toxicity of CDK7 inhibitors such as THZ1 is the main limitation of the clinical *** this work,we synthesized Cys8E(C8E)nanoparticles(NPs)loaded with THZ1(C8E@THZ1),a novel GSH-targeting and stimuli-responsive nano-delivery platform,and investigated its anti-tumor potential and biosafety *** vitro,C8E@THZ1 potently inhibited the proliferation and promoted the apoptosis of prostate cancer *** tumor-bearing mice,C8E@THZ1 inhibited tumors by up to 85%,while the damage of THZ1 to liver function was effectively *** results confirmed that inhibition of CDK7 can effectively block the progression of prostate cancer,and that Cys8E NPs is a highly prospective delivery platform to promote the clinical application of CDK7 inhibitors.

关键词： prostate cancer Nanoparticles CDK7 THZ1 THZ1@Cys8E NPs

The intriguing role of fibroblasts and c-Jun in the chemopreventive and therapeutic effect of finasteride on xenograft models of prostate cancer

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Asian Journal of Andrology 2016年第6期18卷 913-919页

作者： Yi-Nong Niu Kai Wang Song Jin Dong-Dong Fan Ming-Shuai Wang Nian-Zeng Xing Shu-Jie Xia Department of Urology Beijing Chao-Yang Hospital Capital Medical University Beijing China Weifang Hospital of Traditional Chinese Medicine Weifang China Department of Urology Shanghai First Hospital Jiao Tong University Shanghai China

In a large clinical trial, finasteride reduced the rate of low-grade prostate cancer （PCa） while increasing the incidence of high-grade cancer. Whether finasteride promotes the development of high-grade tumors remains controversial. We demonstrated the role of fibroblasts and c-Jun in chemopreventive and therapeutic effect of finasteride on xenograft models of PCa. LNCaP （PC3） cells or recombinants of cancer cells and fibroblasts were implanted in male athymic nude mice treated with finasteride. Tumor growth, cell proliferation, apoptosis, p-Akt, and p-ERKI/2 were evaluated. In LNCaP （PC3） mono-grafted models, finasteride did not change the tumor growth. In recombinant-grafted models, fibroblasts and c-Jun promoted tumor growth; finasteride induced proliferation of LNCaP cells and repressed PC3 cell apoptosis. When c-Jun was knocked out, flbroblasts and/or finasteride did not promote the tumor growth. Finasteride inhibited p-Akt and p-ERKI/2 in mono-culture cancer cells while stimulating the same signaling molecules in the presence of fibroblasts. Reduced p-Akt and p-ERKI/2 were noted in the presence of c-Jun-I- fibroblasts. Fibroblasts and c-Jun promote PCa growth; finasteride further stimulates tumor growth with promoted proliferation, repressed apoptosis, and up-regulated pro-proliferative molecular pathway in the presence of fibroblasts and c-Jun. Stromal-epithelial interactions play critical roles in finasteride＇s therapeutic effects on PCa. Our findings have preliminary implications in using finasteride as a chemopreventive or therapeutic agent for PCa patients.

关键词： chemoprevention c-Jun fibroblasts finasteride mouse model prostate cancer

Incidental prostate cancer in radical cystoprostatectomy specimens

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Asian Journal of Andrology 2008年第5期10卷 809-814页

作者： Xiao-Dong Jin Zhao-Dian Chen Bo Wang Song-Liang Cai Xiao-Lin Yao Bai-Ye Jin Department of Urology The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310003 China Department of Pathology The First Affiliated Hospital Zhejiang University School of Medicine Hangzhou 310003 China

Aim： To investigate the rates of prostate cancer （PCa） in radical cystoprostatectomy （RCP） specimens for bladder cancer in China's Mainland. To determine the follow-up outcome of patients with two concurrent cancers and identify whether prostate-specific antigen （PSA） is a useful tool for the detection of PCa prior to surgery. Methods： From January 2002 to January 2007, 264 male patients with bladder cancer underwent RCP at our center. All patients underwent digital rectal examination （DRE） and B ultrasound. Serum PSA levels were tested in 168 patients. None of the patients had any evidence of PCa before RCP. Entire prostates were embedded and sectioned at 5 mm intervals. Results： Incidental PCa was observed in 37 of 264 （14.0%） RCP specimens. Of these, 12 （32.4%） were clinically significant according to an accepted definition. The PSA levels were not significantly different between patients with PCa and those without PCa, nor between patients with significant PCa and those with insignificant PCa. Thirty-four patients with incidental PCa were followed up. During a mean follow-up period of 26 months, two patients with PSA 〉 4 ng/mL underwent castration. None of the patients died of PCa. Conclusion： The incidence of PCa in RCP specimens in China's Mainland is lower than that in most developed countries. PSA cannot identify asymptomatic PCa prior to RCP. In line with published reports, incidental PCa does not impact the prognosis of bladder cancer patients undergoing RCE

关键词： bladder cancer cystoprostatectomy incidental prostate cancer prostate-specific antigen

Neoadjuvant radiohormonal therapy for oligo-metastatic prostate cancer:safety and efficacy outcomes from an open-label,dose-escalation,single-center,phase Ⅰ/Ⅱ clinical trial

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Frontiers of Medicine 2023年第2期17卷 231-239页

作者： Yifan Chang Xianzhi Zhao Yutian Xiao Shi Yan Weidong Xu Ye Wang Huojun Zhang Shancheng Ren Department of Urology Shanghai Changhai HospitalNaval Medical UniversityShanghai 200433China Department of Radiation Oncology Shanghai Changhai HospitalNaval Medical UniversityShanghai 200433China Department of Urology Shanghai Changzheng HospitalNaval Medical UniversityShanghai 200003China

To evaluate the safety and efficacy of neoadjuvant radiohormonal therapy for oligometastatic prostate cancer(OMPC),we conducted a 3+3 dose escalation,prospective,phase Ⅰ/Ⅱ,single-arm clinical trial(CHiCTR1900025743),in which long-term neoadjuvant androgen deprivation was adopted 1 month before radiotherapy,comprising intensity modulated radiotherapy to the pelvis,and stereotactic body radiation therapy to all extra-pelvic bone metastases for 4‒7 weeks,at 39.6,45,50.4,and 54 ***-assisted radical prostatectomy was performed after 5‒14 *** primary outcome was treatment-related toxicities and adverse events;secondary outcomes were radiological treatment response,positive surgical margin(pSM),postoperative prostate-specific antigen(PSA),pathological down-grading and tumor regression grade,and survival *** patients were recruited from March 2019 to February 2020,aging 66.2 years in average(range,52‒80).Median baseline PSA was 62.0 ng/*** underwent RARP successfully without open *** patients recorded pathological tumor down-staging(83.3%),and 5(41.7%)with cN1 recorded negative regional lymph nodes on final pathology.66.7%(8/12)recorded tumor regression grading(TRG)–Ⅰ and 25%(3/12)recorded TRG-Ⅱ.Median follow-up was 16.5 *** radiological progression-free survival(RPFS)was 21.3 months,with 2-year RPFS of 83.3%.In all,neoadjuvant radiohormonal therapy is well tolerated for oligometastatic prostate cancer.

关键词： neoadjuvant radiotherapy oligometastatic prostate cancer radical prostatectomy

Androgen receptor expression in clinically localized prostate cancer： immunohistochemistry study and literature review

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Asian Journal of Andrology 2008年第6期10卷 855-863页

作者： Yi-Qing Qiu Ivo Leuschner Peter Martin Braun Department of Urology the Second Affliated Hospital of Zhejiang University Hangzhou 310009 China Department of Urology and Pediatric Urology Department of Pathology Universitgitsklinikum Schleswig-Holstein Campus Kiel Kiel 24105 Germany

Aim： To evaluate androgen receptor （AR） expression in clinically localized prostate cancer （PCa）. Methods： Specimens were studied from 232 patients who underwent radical prostatectomy for clinically localized prostatic adenocarcinoma without neoadjuvant hormonal therapy or chemotherapy at our institution between November 2001 and June 2005. Immunohistochemical study was performed using an anti-human AR monoclonal antibody AR441. The mean AR density in the hot spots of different histological areas within the same sections were compared and the correlation of malignant epithelial AR density with clinicopathological parameters such as Gleason score, tumor, nodes and metastases （TNM） stage and pre-treatment prostate-specific antigen （PSA） value was assessed. Results： AR immunoreactivity was almost exclusively nuclear and was observed in tumor cells, non-neoplastic glandular epithelial cells and a proportion of peritumoral and interglandular stromal cells. Mean percentage of AR-positive epithelial cells was significantly higher in cancer tissues than that in normal prostate tissues （mean e SD, 90.0% ± 9.3% vs. 85.3% ±9.7%, P 〈 0.001）. The histological score yielded similar results. The percentage ofAR immunoreactive prostatic cancer nuclei and histological score were not correlated with existing parameters such as Gleason score, tumor, nodes and metastases stage and pre-treatment PSA value in this surgically treated cohort. Conclusion： The results of the present study suggest that there may be limited clinical use for determining AR expression （if evaluated in hot spots） in men with localized PCa.

关键词： androgen receptor prostate cancer immunohistochemistry