title: Up-regulation of insulin-like growth factor-binding protein 3 by 5-fluorouracil (5-FU) leads to the potent anti-proliferative effect of androgen deprivation therapy combined with 5-FU in human prostate cancer cell lines.
abstract: In this study, we investigated the synergistic mechanism of anti-androgen and 5-fluorouracil (5-FU) combination therapy against castration-resistant prostate cancer (CRPC). Four prostate cancer cell lines, LNCaP, 22Rv1, DU145 and PC3, were examined for their growth dependency on androgens and the insulin-like growth factor 1 (IGF1). We assessed the expression changes of certain growth factor receptors and regulating proteins when treated with 5-FU, and found that 5-FU increased the expression of the IGF-binding protein 3 (IGFBP3). Furthermore, 5-FU inhibited the phosphorylation of Akt and p70 S6K, while the knockdown of IGFBP3 reduced the levels of poly (ADP-ribose) polymerase cleaved by 5-FU in PC3 cells. Therefore, the up-regulation of IGFBP3 by 5-FU not only inhibits cell growth by reducing the IGF1 signal but also induces apoptosis in PC3 cells. The synergistic effect of bicalutamide and 5-FU on 22Rv1 cells was reduced by IGFBP3 gene silencing using small-interfering RNA. These results suggest that the up-regulation of IGFBP3 induced by 5-FU plays an important role in the potent anti-tumor effect of 5-FU combined with anti-androgens on CRPC. Androgen-deprivation therapy combined with 5-FU could therefore be an appropriate therapy for CRPC patients.
authors: Department of Medicinal Biotechnology, Institute for Medicinal Resources, Graduate School of Pharmaceutical Sciences, The University of Tokushima, Tokushima 771-0194, Japan. rumi-kawabata@taiho.co.jp
authors: Rumi
authors: R
authors: Kawabata
authors: Shinji
authors: S
authors: Oie
authors: Masayuki
authors: M
authors: Takahashi
authors: Hiroomi
authors: H
authors: Kanayama
authors: Toshinori
authors: T
authors: Oka
authors: Kohji
authors: K
authors: Itoh
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008297:Male; D009570:Nitriles / Q000494:pharmacology; D011471:Prostatic Neoplasms; D034622:RNA Interference; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014105:Tosyl Compounds / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; D000813:Anilides; D000970:Antineoplastic Agents; D018972:Insulin-Like Growth Factor Binding Protein 3; D009570:Nitriles; D017978:Receptors, Growth Factor; D014105:Tosyl Compounds; D007334:Insulin-Like Growth Factor I; C053541:bicalutamide; D005472:Fluorouracil