title: Pin1 Inhibitor Juglone Exerts Anti-Oncogenic Effects on LNCaP and DU145 Cells despite the Patterns of Gene Regulation by Pin1 Differing between These Cell Lines.
abstract: BACKGROUND
  Prostate cancer initially develops in an androgen-dependent manner but, during its progression, transitions to being androgen-independent in the advanced stage. Pin1, one of the peptidyl-prolyl cis/trans isomerases, is reportedly overexpressed in prostate cancers and is considered to contribute to accelerated cell growth, which may be one of the major factors contributing to their androgen-independent growth. Thus, we investigated how Pin1 modulates the gene expressions in both androgen-dependent and androgen-independent prostate cancer cell lines using microarray analysis. In addition, the effects of Juglone, a commercially available Pin1 inhibitor were also examined.
  
  
  METHODS
  Two prostate cancer cell-lines, LNCaP (androgen-dependent) and DU145 (androgen-independent), were treated with Pin1 siRNA and its effects on gene expressions were analyzed by microarray. Individual gene regulations induced by Pin1 siRNA or the Pin1 inhibitor Juglone were examined using RT-PCR. In addition, the effects of Juglone on the growth of LNCaP and DU145 transplanted into mice were investigated.
  
  
  RESULTS
  Microarray analysis revealed that transcriptional factors regulated by Pin1 differed markedly between LNCaP and DU145 cells, the only exception being that Nrf was regulated in the same way by Pin1 siRNA in both cell lines. Despite this marked difference in gene regulations, Pin1 siRNA and Juglone exert a strong inhibitory effect on both the LNCaP and the DU145 cell line, suppressing in vitro cell proliferation as well as tumor enlargement when transplanted into mice.
  
  
  CONCLUSIONS
  Despite Pin1-regulated gene expressions differing between these two prostate cancer cell-lines, LNCaP (androgen-dependent) and DU145 (androgen-independent), Pin1 inhibition suppresses proliferation of both cell-lines. These findings suggest the potential effectiveness of Pin1 inhibitors as therapeutic agents for prostate cancers, regardless of their androgen sensitivity.
authors.affiliation: Department of Medical Chemistry, Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima Japan.
authors.forename: Ryuhei
authors.initials: R
authors.lastname: Kanaoka
authors.affiliation: Division of Diabetes and Metabolism, The Institute for Adult Diseases, Asahi Life Foundation, 1-6-1 Marunouchi, Chiyoda-ku, Tokyo, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Kushiyama
authors.affiliation: Department of Medical Chemistry, Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Seno
authors.affiliation: Department of Medical Chemistry, Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakatsu
authors.affiliation: Department of Medical Chemistry, Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima Japan.
authors.forename: Yasuka
authors.initials: Y
authors.lastname: Matsunaga
authors.affiliation: Department of Medical Chemistry, Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Fukushima
authors.affiliation: Department of Medical Chemistry, Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tsuchiya
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sakoda
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Fujishiro
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamamotoya
authors.affiliation: Department of Medical Chemistry, Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kamata
authors.affiliation: Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Matsubara
authors.affiliation: Department of Medical Chemistry, Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima Japan.
authors.forename: Tomoichiro
authors.initials: T
authors.lastname: Asano
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones; D009363:Neoplasm Proteins; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; C005134:juglone