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Tamoxifen activates cellular phopholipase C and D and elicits protein kinase C translocation
Author(s) -
Cabot Myles C.,
Zhang Zuchuan,
Cao Huiting,
Lavie Yaakov,
Giuliano Armando E.,
Han TieYan,
Jones Ralph C.
Publication year - 1997
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19970304)70:5<567::aid-ijc13>3.0.co;2-a
Subject(s) - tamoxifen , phospholipase d , antiestrogen , protein kinase c , phosphatidylethanol , endocrinology , medicine , phospholipase c , second messenger system , biology , estrogen receptor , signal transduction , chemistry , microbiology and biotechnology , phospholipid , biochemistry , phosphatidic acid , cancer , breast cancer , membrane
The antiestrogen tamoxifen is widely used for endocrine therapy of breast cancer; however, the mechanisms of estrogen receptor‐independent interactions of tamoxifen remain ill defined. Here we examine the effect of tamoxifen on the initial steps of cell signal transduction. To this end, phospholipid metabolism and protein kinase C (PKC) translocation were assessed in CCD986SK human mammary fibroblasts treated with tamoxifen. The addition of tamoxifen resulted in dose‐dependent and time‐dependent increases in the cellular second messengers phosphatidate (PA) and diacylglycerol (DG). On addition of ethanol to the medium, tamoxifen induced the formation of phosphatidylethanol, demonstrating that tamoxifen activates phospholipase D (PLD). Cellular DG also increased in the presence of ethanol, showing that tamoxifen also activates phospholipase C (PLC). In cells prelabeled with choline and ethanolamine, tamoxifen caused increases in choline, phosphorylcholine, ethanolamine and phosphorylethanolamine. Structure‐activity relationship studies for activation of PLD revealed that tamoxifen was the most effective, whereas 4‐ hydroxy tamoxifen was nearly devoid of activity. Phorbol diesters also activated PLD, but estrogen had no influence. Pretreatment of cells with phorbol dibutyrate (PKC down‐regulation protocol) blocked phorbol diester‐ and tamoxifen‐induced PLD activity. Exposure of cells to the PKC inhibitor GF 109203X diminished tamoxifen‐induced PLD activity. Addition of tamoxifen to cultures elicited selective membrane association of PKC ϵ. We conclude that tamoxifen exerts considerable extra‐nuclear influence at the transmembrane signaling level. These events may contribute to effects beyond the scope of estrogen receptor‐dependent actions. The views expressed herein are those of the authors and do not necessarily reflect the views of the US Army, US Navy, Uniformed Services University of the Health Sciences, or the Department of Defense. Int. J. Cancer 70:567–574. © 1997 Wiley‐Liss Inc.