natural proteasome inhibitor celastrol suppresses androgen-independent prostate cancer progression by modulating apoptotic proteins and nf-kappab自然的蛋白酶体抑制剂celastrol抑制androgen-independent通过调节凋亡蛋白质和nf-kappab前列腺癌进展.pdfVIP

Natural Proteasome Inhibitor Celastrol Suppresses Androgen-Independent Prostate Cancer Progression by Modulating Apoptotic Proteins and NF-kappaB 1¤ 1 1,2 1,2 1 3 Yao Dai , Jeffrey DeSano , Wenhua Tang , Xiaojie Meng , Yang Meng , Ezra Burstein , Theodore S. Lawrence1, Liang Xu1,2* 1 Department of Radiation Oncology, Division of Radiation and Cancer Biology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America, 2 Departments of Molecular Biosciences, Urology and Radiation Oncology, University of Kansas Cancer Center, University of Kansas, Lawrence, Kansas, United States of America, 3 Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America Abstract Background: Celastrol is a natural proteasome inhibitor that exhibits promising anti-tumor effects in human malignancies, especially the androgen-independent prostate cancer (AIPC) with constitutive NF-kB activation. Celastrol induces apoptosis by means of proteasome inhibition and suppresses prostate tumor growth. However, the detailed mechanism of action remains elusive. In the current study, we aim to test the hypothesis that celastrol suppresses AIPC progression via inhibiting the constitutive NF-kB activity as well as modulating the Bcl-2 family proteins. Methodology/Principal Findings: We examined the efficacy of celastrol both in vitro and in vivo, and evaluated the role of NF-kB in celastrol-mediated AIPC regression. We found that celastrol inhibited cell proliferation in all three AIPC cell lines (PC-3, DU145 and CL1), with IC50 in the range of 1–2 mM. Celastrol also suppressed cell migration and invasion. Celastrol significantly induced apoptosis as