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Prostate cancer cell growth inhibition by tamoxifen is associated with inhibition of protein kinase C and induction of p21 waf1/cip1
Author(s) -
Rohlff Christian,
Blagosklonny Mikhail V.,
Kyle Edward,
Kesari Anuradha,
Yi Kim Isaac,
Zelner David J.,
Hakim Frances,
Trepel Jane,
Bergan Raymond C.
Publication year - 1998
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/(sici)1097-0045(19980915)37:1<51::aid-pros8>3.0.co;2-b
Subject(s) - growth inhibition , tamoxifen , protein kinase c , antiestrogen , endocrinology , cell growth , du145 , retinoblastoma protein , medicine , cancer research , prostate cancer , biology , transforming growth factor beta , cell cycle , transforming growth factor , kinase , cancer , lncap , breast cancer , microbiology and biotechnology , biochemistry
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 IC 50 s 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. Prostate 37:51–59, 1998. © 1998 Wiley‐Liss, Inc.