The therapeutic and preventive effect of RRR-alpha-vitamin E succinate on prostate cancer via induction of insulin-like growth factor binding protein-3.
OBJECTIVE
Insulin-like growth factor binding protein-3 (IGFBP-3) is a well-known antiproliferative and proapoptotic molecule in prostate cancer, suggesting that targeting IGFBP-3 might produce clinical benefits. In prostate cancer cells, RRR-alpha-vitamin E succinate (VES) inhibits cell proliferation and induces apoptosis, yet the mechanisms remain to be elucidated. We hypothesize that the protective effects of VES in prostate cancer are mediated by IGFBP-3 up-regulation. Using prostate cancer models, the involvement of IGFBP-3 in the anticancer effect of VES was investigated.


METHODS
IGFBP-3 mRNA and protein were determined by real-time PCR and Western blotting in prostate cancer cells, xenografted tumors of nude mice, and prostate tumors of transgenic adenocarcinoma mouse prostate (TRAMP) mice. The serum levels of IGFBP-3 were assessed by ELISA. The importance of IGFBP-3 in VES-mediated antitumor effects was confirmed by small interfering RNA knockdown strategy.


RESULTS
We found that VES induced IGFBP-3 mRNA and protein levels in human prostate cancer cell lines. Knockdown of IGFBP-3 by small interfering RNA attenuated VES-induced IGFBP-3 expression and VES-mediated antiproliferative and proapoptotic functions. Furthermore, administration of VES resulted in a significant therapeutic effect on LNCaP and PC3 xenografts and a preventive effect on tumorigenic progression in the TRAMP model without overt toxicity. Notably, the therapeutic and preventive efficacy of VES correlated with increased accumulation of IGFBP-3 in mouse serum as well as in the xenograft tumors and TRAMP prostate samples. Consequently, reduced proliferation and induced apoptosis were witnessed.


CONCLUSIONS
VES mediates its therapeutic and preventive effects against prostate cancer at least partially through up-regulating IGFBP-3, which inhibits cell proliferation and promotes cell apoptosis.
Yin
Yi
Y
Department of Urology , George Whipple Laboratory for Cancer Research, University of Rochester, Rochester, New York 14642, USA.
Ni
Jing
J
Chen
Ming
M
DiMaggio
Matthew A
MA
Guo
Yinglu
Y
Yeh
Shuyuan
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D024505:Tocopherols; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D018972:Insulin-Like Growth Factor Binding Protein 3; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014810:Vitamin E; D024505:Tocopherols