Natural Proteasome Inhibitor Celastrol Suppresses Androgen-Independent Prostate Cancer Progression by Modulating Apoptotic Proteins and NF-kappaB
dc.contributor.author | Dai, Yao | |
dc.contributor.author | Jeffrey, Tang | |
dc.contributor.author | Wenhua, Xiaojie | |
dc.contributor.author | Meng, Yang | |
dc.contributor.author | Burstein, Ezra | |
dc.contributor.author | Lawrence, Theodore S. | |
dc.contributor.author | Xu, Liang | |
dc.date.accessioned | 2014-03-18T15:48:27Z | |
dc.date.available | 2014-03-18T15:48:27Z | |
dc.date.issued | 2010-12-10 | |
dc.identifier.uri | http://hdl.handle.net/1808/13223 | |
dc.description.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-κB 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-κB 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-κB 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 µM. Celastrol also suppressed cell migration and invasion. Celastrol significantly induced apoptosis as evidenced by increased sub-G1 population, caspase activation and PARP cleavage. Moreover, celastrol promoted cleavage of the anti-apoptotic protein Mcl-1 and activated the pro-apoptotic protein Noxa. In addition, celastrol rapidly blocked cytosolic IκBα degradation and nuclear translocation of RelA. Likewise, celastrol inhibited the expression of multiple NF-κB target genes that are involved in proliferation, invasion and anti-apoptosis. Celastrol suppressed AIPC tumor progression by inhibiting proliferation, increasing apoptosis and decreasing angiogenesis, in PC-3 xenograft model in nude mouse. Furthermore, increased cellular IκBα and inhibited expression of various NF-κB target genes were observed in tumor tissues. Conclusions/Significance Our data suggest that, via targeting the proteasome, celastrol suppresses proliferation, invasion and angiogenesis by inducing the apoptotic machinery and attenuating constitutive NF-κB activity in AIPC both in vitro and in vivo. Celastrol as an active ingredient of traditional herbal medicine could thus be developed as a new therapeutic agent for hormone-refractory prostate cancer. | |
dc.description.sponsorship | This study was supported in part by Department of Defense Prostate Cancer Research Program [W81XWH-06-1-0010] and National Institutes of Health (NIH) National Cancer Institute [R01 CA121830(S1), R21 CA128220 and R01 CA134655] to LX, and by NIH through a University of Michigan Cancer Center Support Grant [5 P30 CA46592]. | |
dc.publisher | Public Library of Science | |
dc.rights | ©2010 Dai et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Apoptosis | |
dc.subject | Cancer treatment | |
dc.subject | Cell migration | |
dc.subject | DU145 cells | |
dc.subject | Gene targeting | |
dc.subject | Prostate cancer | |
dc.subject | Proteasome inhibitors | |
dc.subject | Proteasomes | |
dc.title | Natural Proteasome Inhibitor Celastrol Suppresses Androgen-Independent Prostate Cancer Progression by Modulating Apoptotic Proteins and NF-kappaB | |
dc.type | Article | |
kusw.kuauthor | Tang, Wenhua | |
kusw.kuauthor | Meng, Xiaojie | |
kusw.kuauthor | Liang, Xu | |
kusw.kudepartment | Molecular Biosciences | |
kusw.oastatus | fullparticipation | |
dc.identifier.doi | 10.1371/journal.pone.0014153 | |
kusw.oaversion | Scholarly/refereed, publisher version | |
kusw.oapolicy | This item meets KU Open Access policy criteria. | |
dc.rights.accessrights | openAccess |
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Except where otherwise noted, this item's license is described as: ©2010 Dai et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.