Tamoxifen induces selective membrane association of protein kinase C epsilon in MCF-7 human breast cancer cells.
Tamoxifen, a synthetic antiestrogen, is known for its antitumoral action in vivo; however, it is well accepted that many tamoxifen effects are elicited via estrogen receptor-independent routes. Previously, we reported that tamoxifen induces PKC translocation in fibroblasts. In the present study, we investigated the influence of tamoxifen, and several triphenylethylene derivatives, on protein kinase C (PKC) in MCF-7 human breast cancer cells. As measured by Western blot analysis, tamoxifen elicited isozyme-specific membrane association of PKC-epsilon, which was time-dependent (as early as 5 min post-treatment) and dose-dependent (5.0-20 microM). Tamoxifen did not influence translocation of alpha, beta, gamma, delta or zeta PKC isoforms. Structure-activity relationship studies demonstrated chemical requirements for PKC-epsilon translocation, with tamoxifen, 3-OH-tamoxifen and clomiphene being active. Compounds without the basic amino side chain, such as triphenylethylene, or minus a phenyl group, such as N,N-dimethyl-2-[(4-phenylmethyl)phenoxy]ethanamine, were not active. In vitro cell growth assays showed a correlation between agent-induced PKC-epsilon translocation and inhibition of cell growth. Exposure of cells to clomiphene resulted in apoptosis. Since PKC-epsilon has been associated with cell differentiation and cellular growth-related processes, the antiproliferative influence of tamoxifen on MCF-7 cells may be related to the interaction with PKC-epsilon.
John Wayne Cancer Institute at Saint John's Health Center, Eisenberg-Keefer Breast Cancer Center, Santa Monica, CA 90404, USA.
Y
Y
Lavie
Z C
ZC
Zhang
H T
HT
Cao
T Y
TY
Han
R C
RC
Jones
Y Y
YY
Liu
M
M
Jarman
I R
IR
Hardcastle
A E
AE
Giuliano
M C
MC
Cabot
D018931:Antineoplastic Agents, Hormonal / Q000493:pharmacokinetics / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D011493:Protein Kinase C / Q000187:drug effects* / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000201:enzymology
D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D011493:Protein Kinase C