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Carcinogenesis Advance Access originally published online on March 14, 2006
Carcinogenesis 2006 27(7):1349-1357; doi:10.1093/carcin/bgi380
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Specific positive and negative effects of FLIP on cell survival in human prostate cancer

Keiji Shimada, Mitsutoshi Nakamura, Syuichi Matsuyoshi, Eiwa Ishida and Noboru Konishi *

Department of Pathology, Nara Medical University School of Medicine, Nara, 634-8521, Japan

* To whom correspondence should be addressed. Tel: +81-744-22-3051; Fax: +81-744-23-5687; Email: nkonishi{at}naramed-u.ac.jp

We demonstrate here for the first time novel positive and negative effects of the FLICE-like inhibitory protein (FLIP) on human prostate cancer cell survival. A proteaosome inhibitor, MG132, mediated cell cycle arrest at G2/M and apoptosis through p38 activation. Interestingly, FLIP was stabilized by MG132 and interacted with Raf-1, resulting in enhancement of p38 signals and cytotoxicity. In contrast, overexpression of FLIP inhibited ubiquitylation and proteasomal degradation of ß-catenin, resulting in increase of the target gene cyclin D1, colony formation and invasive activity. Immunohistochemical analysis and in vitro experiments in primary culture showed FLIP to be overexpressed, statistically associated with expression of ß-catenin/cyclin D1 in metastatic cells, the FLIP/ß-catenin/cyclin D1 signals contributing to colony formation and invasion, which were canceled by FLIP knock down. In contrast, MG132-induced cytotoxicity including apoptosis was strongly inhibited by reduction of FLIP. Taken together, the results indicate that FLIP plays an important role in development of metastatic prostate cancer by inhibiting proteasomal degradation of ß-catenin, whereas it is mainly involved in proteasome inhibitior-mediated cell cycle arrest and apoptosis through activating the Raf-1/p38 pathway. Furthermore, proteasome inhibitors may be effective drugs for advanced prostate cancers overexpressing FLIP.


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