title: Phospholipase C-protein kinase C mediated phospholipase D activation pathway is involved in tamoxifen induced apoptosis.
abstract: Tamoxifen (TAM) is the endocrine therapeutic agent the most widely used in the treatment of breast cancer, and it operates primarily through the induction of apoptosis. In this study, we attempted to elucidate the non-ER mediated mechanism behind TAM treatment, involving the phospholipase C-protein kinase C (PLC-PKC) mediated phospholipase D (PLD) activation pathway, using multimodality methods. In TAM treated MCF7 cells, the PLC and PLD protein and mRNA levels increased. Phosphatidylethanol (PEt) and diacylglycerol (DAG) generation also increased, showing increased activity of PLD and PLCgamma1. Translocation of PKCalpha, from cytosol to membrane, was observed in TAM treated cells. By showing that both PKC and PLC inhibitors could reduce the effects of TAM-induced PLD activation, we confirmed the role of PKC and PLC as upstream regulators of PLD. Finally, we demonstrated that TAM treatment reduced the viability of MCF7 cells and brought about rapid cell death. From these results, we confirmed the hypothesis that TAM induces apoptosis in breast cancer cells, and that the signal transduction pathway, involving PLD, PLC, and PKC, constitutes one of the possible mechanisms underlying the non-ER mediated effects associated with TAM.
authors.affiliation: Cancer Research Institute, College of Medicine, Seoul National University, Seoul 110-744, Korea.
authors.forename: Soo-Jung
authors.initials: SJ
authors.lastname: Ahn
authors.forename: Mee-Sup
authors.initials: MS
authors.lastname: Yoon
authors.forename: Shin
authors.initials: S
authors.lastname: Hyuk
authors.forename: Wonshik
authors.initials: W
authors.lastname: Han
authors.forename: Yong-Dal
authors.initials: YD
authors.lastname: Yoon
authors.forename: Joong-Soo
authors.initials: JS
authors.lastname: Han
authors.forename: Dong-Young
authors.initials: DY
authors.lastname: Noh
mesh_terms: D001483:Base Sequence; D017931:DNA Primers; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D010739:Phospholipase D / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D004791:Enzyme Inhibitors; D013629:Tamoxifen; D011493:Protein Kinase C; D010738:Type C Phospholipases; D010739:Phospholipase D