2,3,7,8‑tetrachlorodibenzo‑p‑dioxin suppresses the growth of human colorectal cancer cells in vitro: Implication of the aryl hydrocarbon receptor signaling

Abstract

Human colorectal cancer is the third most common cancer disease with a 5-year survival rate of 55% in USA in 2016. The investigation to identify novel biomarker factors with molecular classification may provide notable clinical information to prolong the survival of patients with colorectal cancer. The aryl hydrocarbon receptor (AHR) binds the AHR nuclear translocator in the cytoplasm of various types of cells, including liver cells, and then binds to the xenobiotic responsive element on various genes. AHR was initially discovered via its ligand, the polychlorinated hydrocarbon, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The present study was undertaken to determine whether TCDD, an agonist of AHR signaling, impacts the growth of RKO human colorectal cancer cells in vitro. Treatment with TCDD (0.1-100 nM) revealed suppressive effects on colony formation and proliferation of RKO cells, and stimulated death of these cells with subconfluence. These effects of TCDD were abolished by pretreatment with CH223191, an inhibitor of AHR signaling. Western blot analysis demonstrated that TCDD treatment decreased AHR levels and elevated cytochrome P450 family 1 subfamily A member 1 (CYP1A1) levels, indicating a stimulation of AHR signaling. TCDD treatment caused an increase in nuclear factor-κB p65 and β-catenin levels, although it did not have an effect on Ras levels. Notably, TCDD treatment increased the levels of p53, retinoblastoma, p21 and regucalcin, which are depressors of carcinogenesis. Additionally, action of TCDD on cell proliferation and death were not revealed in regucalcin-overexpressing RKO cells, and regucalcin overexpression depressed AHR signaling associated with CYP1A1 expression. Thus, AHR signaling suppresses the growth of colorectal cancer cells, indicating a role as a significant targeting molecule for colorectal cancer.

AhR and Cancer: from Gene Profiling to Targeted Therapy

“…Thus AhR −/− mice spontaneously developed cecal tumors as the result of aberrant β-catenin accumulation [52] [53]. Similarly, treatment with TCDD (0.1-100 nM) diminishes colony formation and proliferation of human colorectal cancer cells [54].…”

Effect of indole-3-carbinol on transcriptional profiling of wound-healing genes in macrophages of systemic lupus erythematosus patients: an RNA sequencing assay

“…22 Thus, high induction of AhR battery genes CYP1A1 (3.75-fold) and CYP1B1 (2.41-fold; Supplemental Figure S1) suggested the successful stimulation of AhR signalling by I3C. 25…”

An aryl hydrocarbon receptor agonist suppresses the growth of human umbilical vein endothelial cells in vitro: Potent effect with polyunsaturated fatty acids

“…42 Epoxy metabolites of DHA have been shown to inhibit angiogenesis, tumour growth and metastasis of HUVEC in vitro. 28 DHA and EPA have been shown to suppress monocyte adhesion to HUVEC 43 and to regulate adhesion molecule expression in HUVEC in vitro, via the involvement of the transcription factor NF-κB. 44 Inhibition of AA metabolism has been shown to block endothelial cell migration and induce apoptosis in vitro.…”

“…We previously demonstrated that TCDD suppressed the proliferation and stimulated the death of human liver cancer HepG2 cells 27 and human colorectal cancer RKO cells 28 in vitro, leading to the suppression of tumour growth. VEC may play a pivotal role in the development of angiogenesis and metastasis of cancer cells.…”