Tamoxifen activates cellular phospholipase C and D and elicits protein kinase C translocation

Int J Cancer. 1997 Mar 4;70(5):567-74. doi: 10.1002/(sici)1097-0215(19970304)70:5<567::aid-ijc13>3.0.co;2-a.


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 epsilon. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Hormonal / pharmacology*
  • Diglycerides / metabolism
  • Down-Regulation
  • Enzyme Activation
  • Humans
  • Hydrolysis
  • Phosphatidic Acids / metabolism
  • Phosphatidylcholines / metabolism
  • Phospholipase D / metabolism*
  • Protein Kinase C / metabolism*
  • Signal Transduction / drug effects
  • Tamoxifen / pharmacology*
  • Type C Phospholipases / metabolism*


  • Antineoplastic Agents, Hormonal
  • Diglycerides
  • Phosphatidic Acids
  • Phosphatidylcholines
  • Tamoxifen
  • Protein Kinase C
  • Type C Phospholipases
  • Phospholipase D