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.

Anti-Cancer Agents in Proliferation and Cell Death: The Calcium Connection

“…Tamoxifen (TM) is an estrogen receptor modulator commonly used for breast cancer prevention and treatment. Data from several sources have identified [Ca 2+ ] i modulation by tamoxifen, consistent with cytotoxicity in tumor cells [89,91,92]. In ZR-75-1 human breast cancer cells, treatment with tamoxifen at a concentration above 2 μM induced an early [Ca 2+ ] i rise due to release from stores as well as entry from extracellular space [91].…”

“…Furthermore, in human osteosarcoma cells a sustained increase in [Ca 2+ ] i due to release of calcium from multiple stores (phospholipase C-independent manner) was recorded following 1 µM tamoxifen treatment [90]. The antiproliferative effect of tamoxifen in human non-melanoma skin cancer cells A431, DJM-1, and HSC-1 is also related to an increase of [Ca 2+ ] i [92].…”

Anti-Cancer Effects of 3, 3’-Diindolylmethane on Human Hepatocellular Carcinoma Cells Is Enhanced by Calcium Ionophore: The Role of Cytosolic Ca2+ and p38 MAPK

“…A23187 is a selective Ca 2+ ionophore and is commonly used to increase [Ca 2+ ] i in intact cells (White and Sacks, 2010). Increased intracellular calcium concentration by calcium ionophore A23187 aggravated the tamoxifen induced-proliferation inhibition in skin squamous cell carcinoma cells (Hasegawa et al, 2018). In the present study, co-treatment with DIM and A23187 at non-cytotoxic levels enhanced the proliferation inhibition of DIM.…”

Tamoxifen Twists Again: On and Off-Targets in Macrophages and Infections

“…Importantly, compelling evidence points to “off-target” responses to the prodrug, tamoxifen, which are mediated by ERα-unrelated, low-affinity effectors described in various cell lineages and physio-pathological conditions. Candidate mediators include PKC (protein kinase C), the transcription factors PPAR γ (peroxisome proliferator-activated receptor gamma), GR (glucocorticoid receptor), STAT1 (signal transducer and activator of transcription 1) and NRF2 (nuclear factor erythroid 2-related factor 2) as well as other undefined targets that regulate calcium homeostasis or lipid and sphingolipid metabolism ( Mésange et al, 2002 ; Kim et al, 2008 ; Matsuoka et al, 2009 ; Jiang et al, 2013 ; Bekele et al, 2016 ; Feng et al, 2017 ; Hasegawa et al, 2018 ; Govindarajah et al, 2019 ; Clifford et al, 2020 ).…”