GCP-mediated growth inhibition and apoptosis of prostate cancer cells via androgen receptor-dependent and -independent mechanisms

Clifford G Tepper, Ruth Louise Vinall, Christopher B. Wee, Lingru Xue, Xu Bao Shi, Rebekah Burich, Philip Mack, Ralph W deVere White

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

BACKGROUND. Genistein combined polysaccharide (GCP) is a nutritional supplement that can inhibit prostate cancer growth experimentally and clinically. It is composed predominantly of the isoflavones genistein, daidzein, and glycitein, which have anti-cancer properties. Although genistein is well studied, the properties of GCP are not well defined. The goal of this work was to better characterize the signaling pathways impacted by GCP in an effort to optimize its efficacy. METHODS. Cell growth and apoptosis were evaluated by MTS proliferation, caspase-based assays, and flow cytometry. Modulation of androgen receptor (AR) levels and activation status of signaling molecules were monitored by immunoblot analysis. AR function was measured by evaluating prostate-specific antigen (PSA) message and protein levels and by reporter assays. RESULTS. GCP inhibited proliferation of androgen-dependent LNCaP and androgen-independent LNCaP-p53GOF and 22Rv1 cell lines in a dose-dependent manner and cells were more responsive in the presence of androgen. GCP markedly suppressed mTOR-p70S6K signaling while Akt and p53 were only modestly modulated. GCP significantly attenuated androgen signaling as evidenced by diminished AR protein levels and a consequent reduction in transcriptional activity and PSA expression. AR expression was enhanced by de-repression of translation with inhibitors of PI3K-Akt-mTOR signaling and by inhibition of proteasome-dependent degradation. Neither inhibitor could counteract GCP-mediated AR downregulation, suggesting the involvement of a mechanism(s) independent of these pathways. CONCLUSIONS. Our results suggest that GCP mediates growth inhibition and apoptosis through multiple mechanisms including (1) molecular mimicry of androgen ablation (via AR downregulation) and (2) by providing an AR-independent, pro-apoptotic signal (mTOR inhibition).

Original languageEnglish (US)
Pages (from-to)521-535
Number of pages15
JournalProstate
Volume67
Issue number5
DOIs
StatePublished - Apr 1 2007

Fingerprint

Androgen Receptors
Prostatic Neoplasms
Apoptosis
Androgens
Growth
Genistein
Prostate-Specific Antigen
Down-Regulation
Molecular Mimicry
70-kDa Ribosomal Protein S6 Kinases
Isoflavones
genistein combined polysaccharide
Proteasome Endopeptidase Complex
Caspases
Phosphatidylinositol 3-Kinases
Flow Cytometry
Proteins
Cell Line

Keywords

  • Androgen receptor
  • Genistein combined polysaccharide
  • mTOR
  • p70 S6 kinase
  • Prostate cancer
  • Proteasome

ASJC Scopus subject areas

  • Urology

Cite this

GCP-mediated growth inhibition and apoptosis of prostate cancer cells via androgen receptor-dependent and -independent mechanisms. / Tepper, Clifford G; Vinall, Ruth Louise; Wee, Christopher B.; Xue, Lingru; Shi, Xu Bao; Burich, Rebekah; Mack, Philip; deVere White, Ralph W.

In: Prostate, Vol. 67, No. 5, 01.04.2007, p. 521-535.

Research output: Contribution to journalArticle

Tepper, Clifford G ; Vinall, Ruth Louise ; Wee, Christopher B. ; Xue, Lingru ; Shi, Xu Bao ; Burich, Rebekah ; Mack, Philip ; deVere White, Ralph W. / GCP-mediated growth inhibition and apoptosis of prostate cancer cells via androgen receptor-dependent and -independent mechanisms. In: Prostate. 2007 ; Vol. 67, No. 5. pp. 521-535.
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abstract = "BACKGROUND. Genistein combined polysaccharide (GCP) is a nutritional supplement that can inhibit prostate cancer growth experimentally and clinically. It is composed predominantly of the isoflavones genistein, daidzein, and glycitein, which have anti-cancer properties. Although genistein is well studied, the properties of GCP are not well defined. The goal of this work was to better characterize the signaling pathways impacted by GCP in an effort to optimize its efficacy. METHODS. Cell growth and apoptosis were evaluated by MTS proliferation, caspase-based assays, and flow cytometry. Modulation of androgen receptor (AR) levels and activation status of signaling molecules were monitored by immunoblot analysis. AR function was measured by evaluating prostate-specific antigen (PSA) message and protein levels and by reporter assays. RESULTS. GCP inhibited proliferation of androgen-dependent LNCaP and androgen-independent LNCaP-p53GOF and 22Rv1 cell lines in a dose-dependent manner and cells were more responsive in the presence of androgen. GCP markedly suppressed mTOR-p70S6K signaling while Akt and p53 were only modestly modulated. GCP significantly attenuated androgen signaling as evidenced by diminished AR protein levels and a consequent reduction in transcriptional activity and PSA expression. AR expression was enhanced by de-repression of translation with inhibitors of PI3K-Akt-mTOR signaling and by inhibition of proteasome-dependent degradation. Neither inhibitor could counteract GCP-mediated AR downregulation, suggesting the involvement of a mechanism(s) independent of these pathways. CONCLUSIONS. Our results suggest that GCP mediates growth inhibition and apoptosis through multiple mechanisms including (1) molecular mimicry of androgen ablation (via AR downregulation) and (2) by providing an AR-independent, pro-apoptotic signal (mTOR inhibition).",
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T1 - GCP-mediated growth inhibition and apoptosis of prostate cancer cells via androgen receptor-dependent and -independent mechanisms

AU - Tepper, Clifford G

AU - Vinall, Ruth Louise

AU - Wee, Christopher B.

AU - Xue, Lingru

AU - Shi, Xu Bao

AU - Burich, Rebekah

AU - Mack, Philip

AU - deVere White, Ralph W

PY - 2007/4/1

Y1 - 2007/4/1

N2 - BACKGROUND. Genistein combined polysaccharide (GCP) is a nutritional supplement that can inhibit prostate cancer growth experimentally and clinically. It is composed predominantly of the isoflavones genistein, daidzein, and glycitein, which have anti-cancer properties. Although genistein is well studied, the properties of GCP are not well defined. The goal of this work was to better characterize the signaling pathways impacted by GCP in an effort to optimize its efficacy. METHODS. Cell growth and apoptosis were evaluated by MTS proliferation, caspase-based assays, and flow cytometry. Modulation of androgen receptor (AR) levels and activation status of signaling molecules were monitored by immunoblot analysis. AR function was measured by evaluating prostate-specific antigen (PSA) message and protein levels and by reporter assays. RESULTS. GCP inhibited proliferation of androgen-dependent LNCaP and androgen-independent LNCaP-p53GOF and 22Rv1 cell lines in a dose-dependent manner and cells were more responsive in the presence of androgen. GCP markedly suppressed mTOR-p70S6K signaling while Akt and p53 were only modestly modulated. GCP significantly attenuated androgen signaling as evidenced by diminished AR protein levels and a consequent reduction in transcriptional activity and PSA expression. AR expression was enhanced by de-repression of translation with inhibitors of PI3K-Akt-mTOR signaling and by inhibition of proteasome-dependent degradation. Neither inhibitor could counteract GCP-mediated AR downregulation, suggesting the involvement of a mechanism(s) independent of these pathways. CONCLUSIONS. Our results suggest that GCP mediates growth inhibition and apoptosis through multiple mechanisms including (1) molecular mimicry of androgen ablation (via AR downregulation) and (2) by providing an AR-independent, pro-apoptotic signal (mTOR inhibition).

AB - BACKGROUND. Genistein combined polysaccharide (GCP) is a nutritional supplement that can inhibit prostate cancer growth experimentally and clinically. It is composed predominantly of the isoflavones genistein, daidzein, and glycitein, which have anti-cancer properties. Although genistein is well studied, the properties of GCP are not well defined. The goal of this work was to better characterize the signaling pathways impacted by GCP in an effort to optimize its efficacy. METHODS. Cell growth and apoptosis were evaluated by MTS proliferation, caspase-based assays, and flow cytometry. Modulation of androgen receptor (AR) levels and activation status of signaling molecules were monitored by immunoblot analysis. AR function was measured by evaluating prostate-specific antigen (PSA) message and protein levels and by reporter assays. RESULTS. GCP inhibited proliferation of androgen-dependent LNCaP and androgen-independent LNCaP-p53GOF and 22Rv1 cell lines in a dose-dependent manner and cells were more responsive in the presence of androgen. GCP markedly suppressed mTOR-p70S6K signaling while Akt and p53 were only modestly modulated. GCP significantly attenuated androgen signaling as evidenced by diminished AR protein levels and a consequent reduction in transcriptional activity and PSA expression. AR expression was enhanced by de-repression of translation with inhibitors of PI3K-Akt-mTOR signaling and by inhibition of proteasome-dependent degradation. Neither inhibitor could counteract GCP-mediated AR downregulation, suggesting the involvement of a mechanism(s) independent of these pathways. CONCLUSIONS. Our results suggest that GCP mediates growth inhibition and apoptosis through multiple mechanisms including (1) molecular mimicry of androgen ablation (via AR downregulation) and (2) by providing an AR-independent, pro-apoptotic signal (mTOR inhibition).

KW - Androgen receptor

KW - Genistein combined polysaccharide

KW - mTOR

KW - p70 S6 kinase

KW - Prostate cancer

KW - Proteasome

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DO - 10.1002/pros.20548

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