Prostate cancer cell growth inhibition by tamoxifen is associated with inhibition of protein kinase C and induction of p21(waf1/cip1).
BACKGROUND
Inhibition of protein kinase C (PKC) and modulation of transforming growth factor-beta (TGF-beta) 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-beta 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 microM, and were not affected by estrogen. Tamoxifen-mediated growth inhibition was not associated with induction of TGF-beta. 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.
Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
C
C
Rohlff
M V
MV
Blagosklonny
E
E
Kyle
A
A
Kesari
I Y
IY
Kim
D J
DJ
Zelner
F
F
Hakim
J
J
Trepel
R C
RC
Bergan
D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D011493:Protein Kinase C / Q000096:biosynthesis / Q000187:drug effects*; D015398:Signal Transduction; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000187:drug effects*
D018931:Antineoplastic Agents, Hormonal; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016212:Transforming Growth Factor beta; D013629:Tamoxifen; D011493:Protein Kinase C