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

Abstract

Given that prolonged exposure to unopposed estrogen has been implicated in endometrial carcinogenesis, our goal was to evaluate the effect of As(2)O(3) on regulation of estrogen receptor-alpha (ERa) expression in endometrial cancer cells. As(2)O(3) inhibited ER- mRNA and protein expression in a dose-dependent manner in both the Ishikawa and ECC-1 endometrial cancer cell lines. Treatment with As(2)O(3) 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 As(2)O(3) counteracted As(2)O(3)'s inhibitory effect on ER- expression. We provide evidence that As(2)O(3) inhibits ER- mRNA and protein expression in endometrial cancer cells, potentially through interaction with the MAPK pathway. Thus, As(2)O(3) may be valuable for its anti-estrogenic activity in combination with its anti-tumorigenic effects and be a novel therapeutic agent for endometrial cancer.

Systematic dissection of dysregulated transcription factor–miRNA feed-forward loops across tumor types

“…In this study, we found that CCND1 was upregulated in most of the tumor types (Figure 6). Meanwhile, ATO has been demonstrated to be an inducer of JUN through regulating JNK and MAPK pathways in many cancers, such as bladder cancer [67], prostate cancer [68], NSCLC [69], liver cancer [70] and endometrial cancer [71]. Here, JUN was downregulated in almost all tumor types in our pan-cancer analysis (Figure 6).…”

Chronic exposure to arsenic, LINE-1 hypomethylation, and blood pressure: a cross-sectional study in Bangladesh

“…Cell line experiments demonstrated that the methylation levels of LINE-1 were decreased by treatment with estradiol but not with dihydrotestosterone [57]. Arsenic exposure has been reported to have endocrine-disruptive effects [58, 59], and it may thus be likely that arsenic causes hypomethylation through its endocrine-disrupting activity.…”

microRNA expression alteration after arsenic trioxide treatment in HepG‐2 cells

“…These successful cases prompted investigations to elucidate the mechanisms of action underlying these clinical responses. Proposed mechanisms for ATO's antitumorigenic effects include induction of apoptosis through its effects on caspases, inhibition of cell growth through its interactions with multiple signaling pathways including the mitogen‐activated protein kinase pathway, promotion of cell differentiation, and inhibition of angiogenesis via downregulation of vascular endothelial growth factor production 9,10 . In spite of its efficacy in various cancers, ATO is also a toxic agent: chronic exposure to ATO has resulted in numerous pathogeneses such as lung cancer, peripheral nerve effects and cardiovascular changes 11–13 .…”

“…Proposed mechanisms for ATO's antitumorigenic effects include induction of apoptosis through its effects on caspases, inhibition of cell growth through its interactions with multiple signaling pathways including the mitogen-activated protein kinase pathway, promotion of cell differentiation, and inhibition of angiogenesis via downregulation of vascular endothelial growth factor production. 9,10 In spite of its efficacy in various cancers, ATO is also a toxic agent: chronic exposure to ATO has resulted in numerous pathogeneses such as lung cancer, peripheral nerve effects and cardiovascular changes. [11][12][13] In some studies, the ATO concentrations required to take effect were much higher than the physiologically tolerable concentrations, which limited its clinical application.…”