Document Detail

Androgen suppresses proliferation of castration-resistant LNCaP 104-R2 prostate cancer cells through androgen receptor, Skp2, and c-Myc.
MedLine Citation:
PMID:  21781227     Owner:  NLM     Status:  MEDLINE    
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.
Chih-Pin Chuu; John M Kokontis; Richard A Hiipakka; Junichi Fukuchi; Hui-Ping Lin; Ching-Yu Lin; Chieh Huo; Chiech Huo; Liang-Cheng Su; Shutsung Liao
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-08-18
Journal Detail:
Title:  Cancer science     Volume:  102     ISSN:  1349-7006     ISO Abbreviation:  Cancer Sci.     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-10-24     Completed Date:  2011-12-19     Revised Date:  2014-09-11    
Medline Journal Info:
Nlm Unique ID:  101168776     Medline TA:  Cancer Sci     Country:  England    
Other Details:
Languages:  eng     Pagination:  2022-8     Citation Subset:  IM    
Copyright Information:
© 2011 Japanese Cancer Association.
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MeSH Terms
Adenocarcinoma / metabolism,  pathology*,  secondary
Androgen Antagonists / pharmacology,  therapeutic use
Anilides / pharmacology,  therapeutic use
Cell Cycle / drug effects
Cell Division
Cell Line, Tumor / drug effects,  metabolism,  pathology
Cyclin-Dependent Kinase Inhibitor p27 / biosynthesis,  genetics,  physiology
Drug Implants
Gene Expression Regulation, Neoplastic / drug effects*
Lymphatic Metastasis
Metribolone / pharmacology
Mice, Inbred BALB C
Mice, Nude
Neoplasm Proteins / biosynthesis,  genetics,  physiology*
Nitriles / pharmacology,  therapeutic use
Prostatic Neoplasms / metabolism,  pathology*
Proto-Oncogene Proteins c-myc / biosynthesis,  genetics,  physiology*
Receptors, Androgen
S-Phase Kinase-Associated Proteins / biosynthesis,  genetics,  physiology*
Testosterone / administration & dosage,  pharmacology
Tosyl Compounds / pharmacology,  therapeutic use
Xenograft Model Antitumor Assays
Grant Support
CA58073/CA/NCI NIH HHS; R01 CA058073/CA/NCI NIH HHS; R01 CA058073-19/CA/NCI NIH HHS
Reg. No./Substance:
0/Androgen Antagonists; 0/Anilides; 0/Drug Implants; 0/MYC protein, human; 0/Neoplasm Proteins; 0/Nitriles; 0/Proto-Oncogene Proteins c-myc; 0/Receptors, Androgen; 0/S-Phase Kinase-Associated Proteins; 0/Tosyl Compounds; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 2C323EGI97/Metribolone; 3XMK78S47O/Testosterone; 90357-06-5/bicalutamide
Erratum In:
Cancer Sci. 2013 Jan;104(1):142
Note: Huo, Chiech [corrected to Huo, Chieh]

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