3,3′-Diindolylmethane Suppressed Cyprodinil-Induced Epithelial-Mesenchymal Transition and Metastatic-Related Behaviors of Human Endometrial Ishikawa Cells via an Estrogen Receptor-Dependent Pathway

Abstract

Cyprodinil (CYP) is a pyrimidine amine fungicide that has been extensively used in agricultural areas. 3,3 -Diindolylmethane (DIM) is a derivative of the dietary phytoestrogen, indole-3-carbinol (I3C), which is derived from cruciferous vegetables and considered to be a cancer-preventive phytonutrient agent. In this study, the effects of CYP and DIM were examined on the cell viability, invasion, and metastasis of human endometrial cancer cells, Ishikawa, via epithelial mesenchymal transition (EMT). CYP increased the level of cell viability of Ishikawa cells compared to DMSO as a control, as did E2. Ishikawa cells lost cell-to-cell contact and obtained a spindle-shaped or fibroblast-like morphology in response to the application of E2 or CYP by the cell morphology assay. In the cell migration and invasion assay, CYP enhanced the ability of migration and invasion of Ishikawa cells, as did E2. E2 and CYP increased the expressions of N-cadherin and Snail proteins, while decreasing the expression of E-cadherin protein as EMT-related markers. In addition, E2 and CYP increased the protein expressions of cathepsin D and MMP-9, metastasis-related markers. Conversely, CYP-induced EMT, cell migration, and invasion were reversed by fulvestrant (ICI 182,780) as an estrogen receptor (ER) antagonist, indicating that CYP exerts estrogenic activity by mediating these processes via an ER-dependent pathway. Similar to ICI 182,780, DIM significantly suppressed E2 and CYP-induced proliferation, EMT, migration, and invasion of Ishikawa cancer cells. Overall, the present study revealed that DIM has an antiestrogenic chemopreventive effect to withdraw the cancer-enhancing effect of E2 and CYP, while CYP has the capacity to enhance the metastatic potential of estrogen-responsive endometrial cancer.

3,3′-Diindolylmethane modulates aryl hydrocarbon receptor of esophageal squamous cell carcinoma to reverse epithelial-mesenchymal transition through repressing RhoA/ROCK1-mediated COX2/PGE2 pathway

“…Aryl hydrocarbon receptor is a ligand-dependent transcription factor which has been reported to have connections with tumor metastasis of thyroid carcinoma, neuroblastoma and inflammatory breast cancer [22][23][24]. And DIM as a selective modulator of AHR, has been demonstrated it has inhibitory effects on tumor proliferation, migration and invasion [25,26]. Meanwhile, our previous study have demonstrated that AHR overexpression contributed to worse functional phenotypes and DIM treatment could inhibit ESCC cell growth, induce G1 phase arrest and promote cell apoptosis of TE1 cells [10].…”

SWATH-MS Analysis of FFPE Tissues Identifies Stathmin as a Potential Marker of Endometrial Cancer in Patients Exposed to Tamoxifen

“…First, the analysis of differential abundance in 34 EC samples versus 11 control myometrium tissues identified 431 up- and 115 down-regulated proteins (|log2 FC| > 0.58, FDR-adjusted p -value <0.05, Data File S3A). Among these, a number of proteins biologically relevant for endometrial cancer development ,− were found. Ordered according to log2 FC (Data File S3A), the more abundant proteins in tumor versus normal tissues included calcyphosin (CAPS), myeloblastin (PRTN3), high mobility group protein HMGI-C (HMGA2), pyruvate kinase (PKM), azurocidin (AZU), annexin A2 (ANXA2), cathepsin B (CTSB), 14–3–3 σ (SFN), S100A8, lactotransferrin (LTF), cathepsin D (CTSD), and stathmin (STMN1).…”

Mechanism of epithelial‐mesenchymal transition in cancer and its regulation by natural compounds

“…In another study, an N‐glycosylated derivative of DIM attenuated EMT by potently inducing Par4 (a proapoptotic protein) in pancreatic cancer cells 454 . Interestingly, DIM also reduced the proliferation, invasion, migration, metastasis, and EMT of endometrial cancer cells by suppressing the estrogen‐receptor‐dependent pathway 455 . In estrogen‐receptor‐positive breast cancer cells, DIM abrogated migration, invasion, and EMT induced by endocrine‐disrupting chemicals such as triclosan and bisphenol A by suppressing CXCR4 protein expression 456 .…”

“…454 Interestingly, DIM also reduced the proliferation, invasion, migration, metastasis, and EMT of endometrial cancer cells by suppressing the estrogen-receptor-dependent pathway. 455 In estrogen-receptor-positive breast cancer cells, DIM abrogated migration, invasion, and EMT induced by endocrine-disrupting chemicals such as triclosan and bisphenol…”