title: Molecular mechanisms of synergistic induction of apoptosis by the combination therapy with hyperthermia and cisplatin in prostate cancer cells.
abstract: Prostate Cancer has become the second leading cause of male cancer-related incidence and mortality in United States. Hyperthermia (HT) is known to serve as a powerful tool in treatment of prostate cancer in clinical. The combination treatment with HT and cisplatin has a synergistic effect to inhibit prostate cancer progression and demonstrates better clinical effectiveness than HT or chemotherapy alone. But molecular mechanisms of this phenomenon have not been illuminated clearly. In this study, we used MTS assay to examine cell viabilities of PC-3, LNCaP, DU-145 and RM-1 cells after treated by HT and cisplatin. Then colony formation of PC-3 and DU-145 cells after treated with HT and cisplatin were photographed. To investigate whether the combination therapy would enhance apoptosis of PC-3 and DU-145 cells, we used Western blot analysis to detect expression level of proteins on apoptosis-regulated signaling pathway in PC-3 and DU-145 cells. Our results showed that the combination treatment decreased cell viabilities and colony formation of prostate cancer cells in a dose-dependent manner and this combination therapy enhanced apoptosis of PC-3 and DU-145 cells via activation of Caspase-3 and cleavage of PARP. We also found that the combination therapy could down-regulate the anti-apoptotic Bcl-2 and IAP family proteins. At last, the combination therapy activated AMPKα-JNK signaling pathway and inhibited Akt-mTOR-p70s6k signaling pathway to promote apoptosis of PC-3 and DU-145 cells. In conclusion, this study clearly elucidated how the combination therapy with HT and cisplatin promoted apoptosis of prostate cancer cells in synergy.
authors.affiliation: Laboratory of Tumor Targeted Therapy, Shanghai Advanced Research Institute, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Jian-Fu
authors.initials: JF
authors.lastname: Zhang
authors.affiliation: Laboratory of Tumor Targeted Therapy, Shanghai Advanced Research Institute, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: Xiang-Ming
authors.initials: XM
authors.lastname: Yan
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Lan
authors.affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yin-Rui
authors.initials: YR
authors.lastname: Lei
authors.affiliation: Laboratory of Tumor Targeted Therapy, Shanghai Advanced Research Institute, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China; Academy of Life Science, Shanghai University, Shanghai, China.
authors.forename: Xiao-Hu
authors.initials: XH
authors.lastname: Li
authors.affiliation: Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: gyfslm@yahoo.com.
authors.forename: Yi-Feng
authors.initials: YF
authors.lastname: Guo
authors.affiliation: Laboratory of Tumor Targeted Therapy, Shanghai Advanced Research Institute, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China; Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: guof@sari.ac.cn.
authors.forename: Fang
authors.initials: F
authors.lastname: Guo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006358:Hot Temperature; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008297:Male; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D051034:Inhibitor of Apoptosis Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000071137:Poly (ADP-Ribose) Polymerase-1; D053148:Caspase 3; D002945:Cisplatin
keywords: Apoptosis; Cisplatin; Combination therapy; Hyperthermia; Prostate cancer