Prostate cancer cell growth inhibition by tamoxifen is associated with inhibition of protein kinase C and induction of p21(waf1/cip1)

Christian Rohlff, Mikhail V. Blagosklonny, Edward Kyle, Anuradha Kesari, Isaac Yi Kim, David J. Zelner, Frances Hakim, Jane Trepel, Raymond Bergan

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

BACKGROUND. Inhibition of protein kinase C (PKC) and modulation of transforming growth factor-β (TGF-β) are both associated with tamoxifen treatment, and both appear to be important in the regulation of prostate cancer cell growth. Investigations were performed which sought to measure the efficacy, and to elucidate the mechanism of growth inhibition by tamoxifen, in hormone-refractory prostate cancer. METHODS. Growth assays were performed on PC3, PC3-M, and DU145 prostate cancer cells. TGF-β was measured by ELISA; p21(waf1/cip1) and retinoblastoma (Rb) protein levels were measured by Western blot; PKC activity was measured by kinase assay; and effects upon cell cycle were measured by flow cytometric analysis. RESULTS. IC50s for growth inhibition ranged from 5.5-10 μM, and were not affected by estrogen. Tamoxifen-mediated growth inhibition was not associated with induction of TGF-β. However, tamoxifen treatment was associated with inhibition of PKC, which was followed by induction of p21(waf1/cip1), Rb dephosphorylation, and G1/S phase cell cycle arrest. Similar effects were observed with the known PKC inhibitor, Ro31-8220. CONCLUSIONS. These data suggest that micromolar concentrations of tamoxifen inhibit prostate cancer cell growth by inhibition of PKC, resulting in induction of the p21(waf1/cip1) protein.

Original languageEnglish (US)
Pages (from-to)51-59
Number of pages9
JournalProstate
Volume37
Issue number1
DOIs
StatePublished - Sep 15 1998
Externally publishedYes

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Tamoxifen
Protein Kinase C
Prostatic Neoplasms
Transforming Growth Factors
Growth
Retinoblastoma Protein
Retinoblastoma
Protein C Inhibitor
G1 Phase
Protein Kinase Inhibitors
Cell Cycle Checkpoints
S Phase
Cell Cycle
Estrogens
Phosphotransferases
Western Blotting
Enzyme-Linked Immunosorbent Assay
Hormones
Therapeutics
Proteins

Keywords

  • Cell cycle
  • Drug therapy
  • Retinoblastoma
  • Signal transduction
  • Transforming growth factor beta

ASJC Scopus subject areas

  • Urology

Cite this

Prostate cancer cell growth inhibition by tamoxifen is associated with inhibition of protein kinase C and induction of p21(waf1/cip1). / Rohlff, Christian; Blagosklonny, Mikhail V.; Kyle, Edward; Kesari, Anuradha; Kim, Isaac Yi; Zelner, David J.; Hakim, Frances; Trepel, Jane; Bergan, Raymond.

In: Prostate, Vol. 37, No. 1, 15.09.1998, p. 51-59.

Research output: Contribution to journalArticle

Rohlff, Christian ; Blagosklonny, Mikhail V. ; Kyle, Edward ; Kesari, Anuradha ; Kim, Isaac Yi ; Zelner, David J. ; Hakim, Frances ; Trepel, Jane ; Bergan, Raymond. / Prostate cancer cell growth inhibition by tamoxifen is associated with inhibition of protein kinase C and induction of p21(waf1/cip1). In: Prostate. 1998 ; Vol. 37, No. 1. pp. 51-59.
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AU - Blagosklonny, Mikhail V.

AU - Kyle, Edward

AU - Kesari, Anuradha

AU - Kim, Isaac Yi

AU - Zelner, David J.

AU - Hakim, Frances

AU - Trepel, Jane

AU - Bergan, Raymond

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N2 - BACKGROUND. Inhibition of protein kinase C (PKC) and modulation of transforming growth factor-β (TGF-β) are both associated with tamoxifen treatment, and both appear to be important in the regulation of prostate cancer cell growth. Investigations were performed which sought to measure the efficacy, and to elucidate the mechanism of growth inhibition by tamoxifen, in hormone-refractory prostate cancer. METHODS. Growth assays were performed on PC3, PC3-M, and DU145 prostate cancer cells. TGF-β was measured by ELISA; p21(waf1/cip1) and retinoblastoma (Rb) protein levels were measured by Western blot; PKC activity was measured by kinase assay; and effects upon cell cycle were measured by flow cytometric analysis. RESULTS. IC50s for growth inhibition ranged from 5.5-10 μM, and were not affected by estrogen. Tamoxifen-mediated growth inhibition was not associated with induction of TGF-β. However, tamoxifen treatment was associated with inhibition of PKC, which was followed by induction of p21(waf1/cip1), Rb dephosphorylation, and G1/S phase cell cycle arrest. Similar effects were observed with the known PKC inhibitor, Ro31-8220. CONCLUSIONS. These data suggest that micromolar concentrations of tamoxifen inhibit prostate cancer cell growth by inhibition of PKC, resulting in induction of the p21(waf1/cip1) protein.

AB - BACKGROUND. Inhibition of protein kinase C (PKC) and modulation of transforming growth factor-β (TGF-β) are both associated with tamoxifen treatment, and both appear to be important in the regulation of prostate cancer cell growth. Investigations were performed which sought to measure the efficacy, and to elucidate the mechanism of growth inhibition by tamoxifen, in hormone-refractory prostate cancer. METHODS. Growth assays were performed on PC3, PC3-M, and DU145 prostate cancer cells. TGF-β was measured by ELISA; p21(waf1/cip1) and retinoblastoma (Rb) protein levels were measured by Western blot; PKC activity was measured by kinase assay; and effects upon cell cycle were measured by flow cytometric analysis. RESULTS. IC50s for growth inhibition ranged from 5.5-10 μM, and were not affected by estrogen. Tamoxifen-mediated growth inhibition was not associated with induction of TGF-β. However, tamoxifen treatment was associated with inhibition of PKC, which was followed by induction of p21(waf1/cip1), Rb dephosphorylation, and G1/S phase cell cycle arrest. Similar effects were observed with the known PKC inhibitor, Ro31-8220. CONCLUSIONS. These data suggest that micromolar concentrations of tamoxifen inhibit prostate cancer cell growth by inhibition of PKC, resulting in induction of the p21(waf1/cip1) protein.

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