title: Androgen suppresses proliferation of castration-resistant LNCaP 104-R2 prostate cancer cells through androgen receptor, Skp2, and c-Myc.
abstract: Androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, this therapy is associated with several undesired side-effects, including increased risk of cardiovascular diseases. To study if termination of long-term androgen ablation and restoration of testosterone levels could suppress the growth of relapsed hormone-refractory prostate tumors, we implanted testosterone pellets in castrated nude mice carrying androgen receptor (AR)-positive LNCaP 104-R2 cells, which relapsed from androgen-dependent LNCaP 104-S cells after long-term androgen deprivation. 104-R2 tumor xenografts regressed after testosterone pellets were implanted. Of 33 tumors, 24 adapted to elevation of testosterone level and relapsed as androgen-insensitive tumors. Relapsed tumors (R2Ad) expressed less AR and prostate-specific antigen. We then studied the molecular mechanism underlying the androgenic regulation of prostate cancer cell proliferation. Androgen suppresses proliferation of 104-R2 by inducing G(1) cell cycle arrest through reduction of S-phase kinase-associated protein 2 (Skp2) and c-Myc, and induction of p27(Kip1). 104-R2 cells adapted to androgen treatment and the adapted cells, R2Ad, were androgen-insensitive cells with a slower growth rate and low protein level of AR, high levels of c-Myc and Skp2, and low levels of p27(Kip1). Nuclear AR and prostate-specific antigen expression is present in 104-R2 cells but not R2Ad cells when androgen is absent. Overexpression of AR in R2Ad cells regenerated an androgen-repressed phenotype; knockdown of AR in 104-R2 cells generated an androgen-insensitive phenotype. Overexpression of Skp2 and c-Myc in 104-R2 cells blocked the growth inhibition caused by androgens. We concluded that androgens cause growth inhibition in LNCaP 104-R2 prostate cancer cells through AR, Skp2, and c-Myc.
authors.affiliation: Institute of Cellular and System Medicine, Translational Center for Glandular Malignancies, National Health Research Institutes, Miaoli, Taiwan. cpchuu@nhri.org.tw
authors.forename: Chih-Pin
authors.initials: CP
authors.lastname: Chuu
authors.forename: John M
authors.initials: JM
authors.lastname: Kokontis
authors.forename: Richard A
authors.initials: RA
authors.lastname: Hiipakka
authors.forename: Junichi
authors.initials: J
authors.lastname: Fukuchi
authors.forename: Hui-Ping
authors.initials: HP
authors.lastname: Lin
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Lin
authors.forename: Chieh
authors.initials: C
authors.lastname: Huo
authors.forename: Chiech
authors.initials: C
authors.lastname: Huo
authors.forename: Liang-Cheng
authors.initials: LC
authors.lastname: Su
authors.forename: Shutsung
authors.initials: S
authors.lastname: Liao
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology* / Q000556:secondary; D000726:Androgen Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000813:Anilides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D004343:Drug Implants; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011944:Receptors, Androgen; D044786:S-Phase Kinase-Associated Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013739:Testosterone / Q000008:administration & dosage / Q000494:pharmacology; D014105:Tosyl Compounds / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D004343:Drug Implants; C489427:MYC protein, human; D009363:Neoplasm Proteins; D009570:Nitriles; D016271:Proto-Oncogene Proteins c-myc; D011944:Receptors, Androgen; D044786:S-Phase Kinase-Associated Proteins; D014105:Tosyl Compounds; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015741:Metribolone; D013739:Testosterone; C053541:bicalutamide