title: The chemopreventive action of catechins in the TRAMP mouse model of prostate carcinogenesis is accompanied by clusterin over-expression.
abstract: Clusterin (CLU) protein is widely distributed in animal tissues and is involved in many different processes, including apoptosis and neoplastic transformation. Green tea catechins (GTC) are known to exert chemopreventive effects in many cancer models, including transgenic adenocarcinoma mouse prostate (TRAMP) mice that spontaneously develop prostate cancer (CaP). We report here that growth of SV40-immortalized human prostate epithelial cells (PNT1A) as well as tumorigenic, poorly differentiated prostate cancer cells (PC-3) was potently inhibited by EGCG, the major green tea catechin, while normal human prostate epithelial cells were not significantly affected. IC(50) doses of EGCG for 24 h caused caspase cascade activation and CLU protein accumulation in both cells lines but not in normal cells, in which CLU remained undetectable. While 100% of TRAMP mice developed CaP, only 20% of those receiving 0.3% GTC in drinking water developed the neoplasm. In TRAMP mice, the CLU gene was dramatically down-regulated during onset and progression of CaP. In GTC-treated TRAMP mice in which tumor progression was chemoprevented, CLU mRNA and protein progressively accumulated in the prostate gland. CLU dropped again to undetectable levels in animals in which GTC chemoprevention failed and CaP developed. Up-regulation of histone H3 and down-regulation of growth arrest-specific gene 1 (Gas1) mRNAs in CaP-developing TRAMP mice demonstrated a high proliferation rate in tumors, while the opposite occurred in the glands of GTC chemoprevented animals. Failure of GTC chemoprevention caused induction of both histone H3 and Gas1 and down-regulation of CLU. Immunohistochemistry experiments confirmed CLU down-regulation during CaP onset and progression, and CLU sustained expression in chemoprevented TRAMP mice. A possible role for CLU as a novel tumor-suppressor gene in the prostate is thus suggested.
authors.affiliation: Dipartimento di Medicina Sperimentale, Plesso Biotecnologico Integrato, Università di Parma, Via Volturno, 39-43100 Parma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Caporali
authors.forename: Pierpaola
authors.initials: P
authors.lastname: Davalli
authors.forename: Serenella
authors.initials: S
authors.lastname: Astancolle
authors.forename: Domenico
authors.initials: D
authors.lastname: D'Arca
authors.forename: Maurizio
authors.initials: M
authors.lastname: Brausi
authors.forename: Saverio
authors.initials: S
authors.lastname: Bettuzzi
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Corti
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D002392:Catechin / Q000494:pharmacology*; D051152:Clusterin / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011471:Prostatic Neoplasms / Q000517:prevention & control*; D013662:Tea
chemical_list: D016588:Anticarcinogenic Agents; C495243:Clu protein, mouse; D051152:Clusterin; D013662:Tea; D002392:Catechin