Tamoxifen stimulates phospholipase D activity by an estrogen receptor‐independent mechanism

Abstract

The effects of tamoxifen (TAM), a widely used agent in the treatment of breast cancer, were examined on phospholipase D (PLD)-mediated phospholipid hydrolysis. In drug-sensitive MCF-7 human breast carcinoma cells TAM, similar to several well-established activators of PLD, had no effect on phospholipid hydrolysis. In an estrogen receptor-deficient multidrug-resistant subline of MCF-7 cells, TAM preferentially stimulated the hydrolysis of phosphatidylethanolamine; two-fold stimulation required 2.5 or 5/tM TAM in the absence or presence of serum, respectively. In NIH 3T3 fibroblasts significant (4-to 4.8-fold) stimulation of phosphatidylethanolamine and phosphatidylcholine hydrolysis in the presence of serum required 10/tM TAM. These data establish that TAM can stimulate PLD activity by an estrogen receptor-independent mechanism.

Selective Estrogen Receptor (ER) Modulators Differentially Regulate Phospholipase D Catalytic Activity in ER-Negative Breast Cancer Cells

“…Consistent with previous reports we found that tamoxifen stimulates PLD activity in ER-negative cells (Kiss, 1994). Recent studies have implicated the importance of PLD in transformation (Yoshida et al, 1998;Uchida et al, 1999;Fiucci et al, 2000;Noh et al, 2000;Zhao et al, 2000), so it is interesting to note that a widely used therapeutic like tamoxifen has effects on PLD.…”

“…Interestingly, it has been shown that tamoxifen can stimulate cellular PLD activity through an ER-independent mechanism (Kiss, 1994). The proposed mechanism of this tamoxifen stimulation was through the PLD activator PKC, and we wanted to further explore this interaction in vitro.…”

Tamoxifen induces p21WAF1 and p27KIP1 expression in estrogen receptor-negative lung cancer cells

“…Since PKC plays a crucial role in the signaling pathway that promotes cell growth and transformation, it is possible that Tam may block cell proliferation by inhibiting PKC activity. Second, Tam may in¯uence cell growth by modulating the activity of phospholipases and the activation of lipid signaling pathways (Kiss, 1994). Additionally, Tam was found to induce the expression of transforming growth factor-b (Knabbe et al, 1987), to inhibit calmodulin dependent cyclin AMP phosphodiesterases (Rowlands et al, 1990) and to retard the metabolism of glycosphingolipids (Cabot et al, 1996) in dierent cell types.…”

Tamoxifen Modulates Protein Kinase C via Oxidative Stress in Estrogen Receptor-negative Breast Cancer Cells

“…In a recent study, an activation of phospholipase D by micromolar concentrations of Tam in intact cells was reported (54). Several agents, such as nonphorbol tumor promoters, staurosporine, thapsigargin, okadaic acid, and calyculin-A, that promote the release of arachidonic acid have been shown to induce a cytosol-to-membrane translocation of PKC (55,56).…”