TCDD Promotes Lung Tumors via Attenuation of Apoptosis through Activation of the Akt and ERK1/2 Signaling Pathways

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a multiple-site, multiple-species carcinogen that induces cancer in multiple organs. The molecular mechanisms underlying TCDD-induced lung tumorigenesis remain unclear. In the present study, a two-stage lung tumorigenesis model was established by administrating a single low dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) combined with TCDD to female A/J mice. The results indicated that TCDD combined with low-dose NNK has a significant tumor-promoting effect compared with TCDD or low-dose NNK alone. Resistance to apoptosis is a hallmark of cancer and is thought to be one of the tumor-promoting mechanisms regulated by TCDD. We performed an additional series of experiments in the normal human bronchial epithelial cell line Beas2B cells, in which TCDD was combined with the apoptosis inducer staurosporine. Our in vitro results confirmed that TCDD could rescue cells from apoptosis induced by staurosporine. The inhibition of apoptosis is likely mediated by the activation of the Akt and ERK1/2 pathways, as determined by the effectiveness of pathway-specific inhibitors in abrogating the anti-apoptotic activity of TCDD. In conclusion, we demonstrated that TCDD promoted NNK-induced lung tumorigenesis and revealed that TCDD inhibits staurosporine-induced apoptosis, at least in part, through the Akt and ERK1/2 signaling pathways.

Chemopreventive effect of natural dietary compounds on xenobiotic-induced toxicity

“…[ 32 ] documented that TCDD behaves as a nongenotoxic tumor promoter because TCDD was not able to interact with DNA and failed to reveal mutagenic activity in the Ames test [ 33 ]. TCDD is recognized a tumor promoter that is attributed to the blockage of normal cell regeneration, inhibition of damage cell leading to apoptotic cell death, suppression of cell contact inhibition, and induction of inflammation through direct activation of AhR, epidermal growth factor receptor, and nuclear factor-κB signaling pathways [ 34 – 36 ].…”

A Quantitative HILIC–MS/MS Assay of the Metabolic Response of Huh-7 Cells Exposed to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin

“…However, TCDD has also been reported to prevent apoptosis in the MCF 10A cell line due to the inhibition of epidermal growth factor (EGF) [46,47]. Even though the underlying mechanisms remain unclear and require further investigation, sufficient evidence has revealed that TCDD is a potent tumor promoter in the liver and the skin of mice [48,49,50]. In this study, cell viability was determined by MTT assay (Figure 1B), and cytotoxicity of TCDD-treated cells decreased significantly compared with the untreated Huh-7 cells, indicating that the TCDD doses exploited in our study may increase metabolic activity, promote the proliferation, or prevent the apoptosis of Huh-7 cells.…”

Effects of Acute 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Exposure on the Circulating and Cecal Metabolome Profile

“…Extracellular signal-related kinase 1/2 (ERK1/2) is a kinase enzyme that regulates a variety of cell activities including metabolism, proliferation, and survival [ 61 ]. Previous research has demonstrated that TCDD-mediated toxicity in the contexts of cancer and neuropathology is partially dependent on ERK1/2 signaling pathways [ 62 , 63 , 64 ]. Additionally, it has been shown that multiple inhibitors of ERK1/2 can reverse the observed effects of TCDD exposure by regulating the steady-state levels of the AHR and inhibiting cytochrome P450 family 1 subfamily member 1 activity [ 65 ].…”