Androgen Receptor (AR) expression in AR-Negative prostate cancer cells results in differential effects of DHT and IGF-I on proliferation and AR activity between localized and metastatic tumors

Stephen R. Plymate, Marie K. Tennant, Stephen H. Culp, Lillie Woodke, Marco Marcelli, Ilsa Colman, Peter S. Nelson, Julie M. Carroll, Charles Roberts, Joy L. Ware

    Research output: Contribution to journalArticle

    33 Citations (Scopus)

    Abstract

    BACKGROUND. Two features of the progression from organ-confined to metastatic prostate cancer are dysregulation of the androgen receptor (AR) and a decrease in insulin-like growth factor-type-I receptor (IGF-IR) expression. The purpose of this study was to determine the effect of changes in IGF-IR expression on AR activity. METHODS. M12 human prostate cells were stably transfected with an AR expression construct to produce the M12-AR parental (PAR) cell line. PAR cells were implanted orthotopically into nude mice and M12-AR primary (PRI) cell lines were derived from intraprostatic tumors and metastatic cell lines (MET) were derived from PRI tumors that had metastasized to diaphragm or lung. RESULTS. Tumor formation in the prostate by PAR cells was decreased significantly compared to M12 controls. PAR, PRI, and MET cells expressed equivalent amounts of AR protein; however, IGF-IR expression was increased significantly in PAR and PRI cells. IGF-IR expression decreased in MET lines to the levels seen in M12 control cells. IGF-I significantly enhanced dihydrotestosterone (DHT)-stimulated, but not basal, AR transcriptional activity in PRI cells. In MET cells, IGF-I significantly suppressed DHT-stimulated transcriptional activity. In MET cells in which the IGF-IR was re-expressed from a retroviral vector, the effects of DHT and IGF-I on AR activity were similar to those seen in PRI cells. CONCLUSIONS. This study demonstrates that the changes in IGF-IR expression exhibited by this model of metastatic progression cause significant alterations in AR signaling and suggest that this interaction may be an important aspect of the changes seen in AR function in disease progression in vivo.

    Original languageEnglish (US)
    Pages (from-to)276-290
    Number of pages15
    JournalProstate
    Volume61
    Issue number3
    DOIs
    StatePublished - Nov 1 2004

    Fingerprint

    Dihydrotestosterone
    Androgen Receptors
    Insulin-Like Growth Factor I
    Prostatic Neoplasms
    IGF Type 1 Receptor
    Neoplasms
    Prostate
    Cell Line
    Diaphragm
    Tumor Cell Line
    Nude Mice
    Disease Progression
    Lung

    Keywords

    • Androgen receptor
    • IGF-IR
    • Prostate cancer

    ASJC Scopus subject areas

    • Urology

    Cite this

    Androgen Receptor (AR) expression in AR-Negative prostate cancer cells results in differential effects of DHT and IGF-I on proliferation and AR activity between localized and metastatic tumors. / Plymate, Stephen R.; Tennant, Marie K.; Culp, Stephen H.; Woodke, Lillie; Marcelli, Marco; Colman, Ilsa; Nelson, Peter S.; Carroll, Julie M.; Roberts, Charles; Ware, Joy L.

    In: Prostate, Vol. 61, No. 3, 01.11.2004, p. 276-290.

    Research output: Contribution to journalArticle

    Plymate, Stephen R. ; Tennant, Marie K. ; Culp, Stephen H. ; Woodke, Lillie ; Marcelli, Marco ; Colman, Ilsa ; Nelson, Peter S. ; Carroll, Julie M. ; Roberts, Charles ; Ware, Joy L. / Androgen Receptor (AR) expression in AR-Negative prostate cancer cells results in differential effects of DHT and IGF-I on proliferation and AR activity between localized and metastatic tumors. In: Prostate. 2004 ; Vol. 61, No. 3. pp. 276-290.
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    abstract = "BACKGROUND. Two features of the progression from organ-confined to metastatic prostate cancer are dysregulation of the androgen receptor (AR) and a decrease in insulin-like growth factor-type-I receptor (IGF-IR) expression. The purpose of this study was to determine the effect of changes in IGF-IR expression on AR activity. METHODS. M12 human prostate cells were stably transfected with an AR expression construct to produce the M12-AR parental (PAR) cell line. PAR cells were implanted orthotopically into nude mice and M12-AR primary (PRI) cell lines were derived from intraprostatic tumors and metastatic cell lines (MET) were derived from PRI tumors that had metastasized to diaphragm or lung. RESULTS. Tumor formation in the prostate by PAR cells was decreased significantly compared to M12 controls. PAR, PRI, and MET cells expressed equivalent amounts of AR protein; however, IGF-IR expression was increased significantly in PAR and PRI cells. IGF-IR expression decreased in MET lines to the levels seen in M12 control cells. IGF-I significantly enhanced dihydrotestosterone (DHT)-stimulated, but not basal, AR transcriptional activity in PRI cells. In MET cells, IGF-I significantly suppressed DHT-stimulated transcriptional activity. In MET cells in which the IGF-IR was re-expressed from a retroviral vector, the effects of DHT and IGF-I on AR activity were similar to those seen in PRI cells. CONCLUSIONS. This study demonstrates that the changes in IGF-IR expression exhibited by this model of metastatic progression cause significant alterations in AR signaling and suggest that this interaction may be an important aspect of the changes seen in AR function in disease progression in vivo.",
    keywords = "Androgen receptor, IGF-IR, Prostate cancer",
    author = "Plymate, {Stephen R.} and Tennant, {Marie K.} and Culp, {Stephen H.} and Lillie Woodke and Marco Marcelli and Ilsa Colman and Nelson, {Peter S.} and Carroll, {Julie M.} and Charles Roberts and Ware, {Joy L.}",
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    TY - JOUR

    T1 - Androgen Receptor (AR) expression in AR-Negative prostate cancer cells results in differential effects of DHT and IGF-I on proliferation and AR activity between localized and metastatic tumors

    AU - Plymate, Stephen R.

    AU - Tennant, Marie K.

    AU - Culp, Stephen H.

    AU - Woodke, Lillie

    AU - Marcelli, Marco

    AU - Colman, Ilsa

    AU - Nelson, Peter S.

    AU - Carroll, Julie M.

    AU - Roberts, Charles

    AU - Ware, Joy L.

    PY - 2004/11/1

    Y1 - 2004/11/1

    N2 - BACKGROUND. Two features of the progression from organ-confined to metastatic prostate cancer are dysregulation of the androgen receptor (AR) and a decrease in insulin-like growth factor-type-I receptor (IGF-IR) expression. The purpose of this study was to determine the effect of changes in IGF-IR expression on AR activity. METHODS. M12 human prostate cells were stably transfected with an AR expression construct to produce the M12-AR parental (PAR) cell line. PAR cells were implanted orthotopically into nude mice and M12-AR primary (PRI) cell lines were derived from intraprostatic tumors and metastatic cell lines (MET) were derived from PRI tumors that had metastasized to diaphragm or lung. RESULTS. Tumor formation in the prostate by PAR cells was decreased significantly compared to M12 controls. PAR, PRI, and MET cells expressed equivalent amounts of AR protein; however, IGF-IR expression was increased significantly in PAR and PRI cells. IGF-IR expression decreased in MET lines to the levels seen in M12 control cells. IGF-I significantly enhanced dihydrotestosterone (DHT)-stimulated, but not basal, AR transcriptional activity in PRI cells. In MET cells, IGF-I significantly suppressed DHT-stimulated transcriptional activity. In MET cells in which the IGF-IR was re-expressed from a retroviral vector, the effects of DHT and IGF-I on AR activity were similar to those seen in PRI cells. CONCLUSIONS. This study demonstrates that the changes in IGF-IR expression exhibited by this model of metastatic progression cause significant alterations in AR signaling and suggest that this interaction may be an important aspect of the changes seen in AR function in disease progression in vivo.

    AB - BACKGROUND. Two features of the progression from organ-confined to metastatic prostate cancer are dysregulation of the androgen receptor (AR) and a decrease in insulin-like growth factor-type-I receptor (IGF-IR) expression. The purpose of this study was to determine the effect of changes in IGF-IR expression on AR activity. METHODS. M12 human prostate cells were stably transfected with an AR expression construct to produce the M12-AR parental (PAR) cell line. PAR cells were implanted orthotopically into nude mice and M12-AR primary (PRI) cell lines were derived from intraprostatic tumors and metastatic cell lines (MET) were derived from PRI tumors that had metastasized to diaphragm or lung. RESULTS. Tumor formation in the prostate by PAR cells was decreased significantly compared to M12 controls. PAR, PRI, and MET cells expressed equivalent amounts of AR protein; however, IGF-IR expression was increased significantly in PAR and PRI cells. IGF-IR expression decreased in MET lines to the levels seen in M12 control cells. IGF-I significantly enhanced dihydrotestosterone (DHT)-stimulated, but not basal, AR transcriptional activity in PRI cells. In MET cells, IGF-I significantly suppressed DHT-stimulated transcriptional activity. In MET cells in which the IGF-IR was re-expressed from a retroviral vector, the effects of DHT and IGF-I on AR activity were similar to those seen in PRI cells. CONCLUSIONS. This study demonstrates that the changes in IGF-IR expression exhibited by this model of metastatic progression cause significant alterations in AR signaling and suggest that this interaction may be an important aspect of the changes seen in AR function in disease progression in vivo.

    KW - Androgen receptor

    KW - IGF-IR

    KW - Prostate cancer

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    U2 - 10.1002/pros.20099

    DO - 10.1002/pros.20099

    M3 - Article

    VL - 61

    SP - 276

    EP - 290

    JO - Prostate

    JF - Prostate

    SN - 0270-4137

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    ER -