Arsenic Trioxide (As2O3) Inhibits Expression of Estrogen Receptor-alpha Through Regulation of the Mitogen-activated Protein Kinase (MAPK) Pathway in Endometrial Cancer Cells

Given that prolonged exposure to unopposed estrogen has been implicated in endometrial carcinogenesis, our goal was to evaluate the effect of As2O3 on regulation of estrogen receptor-alpha (ERa) expression in endometrial cancer cells. As2O3 inhibited ER- mRNA and protein expression in a dose-dependent manner in both the Ishikawa and ECC-1 endometrial cancer cell lines. Treatment with As2O3 resulted in rapid phosphorylation of the p42/p44 MAPK which could be abolished by addition of the MAPK inhibitor, U0126. Although treatment with U0126 alone resulted in up-regulation of ER- mRNA and protein, exposure to U0126 in combination with As2O3 counteracted As2O3's inhibitory effect on ER- expression. We provide evidence that As2O3 inhibits ER- mRNA and protein expression in endometrial cancer cells, potentially through interaction with the MAPK pathway. Thus, As2O3 may be valuable for its anti-estrogenic activity in combination with its anti-tumor genic affects and be a novel therapeutic agent for endometrial cancer.