Tamoxifen inhibits the proliferation of non-melanoma skin cancer cells by increasing intracellular calcium concentration

Abstract

Tamoxifen is an estrogen receptor (ER) antagonist used as first-line chemotherapy in breast cancer. Recent studies suggest that tamoxifen may be effective not only for ER-positive but also for ER-negative cancer cases. The aim of the present study was to investigate the antiproliferative effect of tamoxifen against human non-melanoma skin cancer cells. Tamoxifen inhibited the proliferation of the skin squamous cell carcinoma (SCC) cell lines A431, DJM-1 and HSC-1. A431 cells did not express ER-α or-β, suggesting that tamoxifen may exert antiproliferative effects on skin SCC cells via a non-ER-mediated pathway. Tamoxifen increased the intracellular calcium concentration of skin SCC cells, and this increase in intracellular calcium concentration by calcium ionophore A23187 suppressed the proliferation of skin SCC cells. These data indicate that tamoxifen inhibited the proliferation of human skin SCC cells via increasing intracellular calcium concentration. Voltage-gated calcium channels and non-selective cation channels are involved in the increase in intracellular calcium concentration induced by tamoxifen. The broad-spectrum protein kinase C (PKC) inhibitor phloretin significantly attenuated the antiproliferative effect of tamoxifen on skin SCC cells. From these data, it may be concluded that tamoxifen inhibits the proliferation of skin SCC cells by induction of extracellular calcium influx via calcium channels in the plasma membrane and by subsequent activation of PKC.