TCDD promotes lung tumors via attenuation of apoptosis through activation of the Akt and ERK1/2 signaling pathways.

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.

The regulation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumor promotion by estradiol in female A/J mice.

Epidemiological studies indicate that women are at a higher risk developing lung cancer than men are. It is suggested that estrogen is one of the most important factors in lung cancer development in females. Additionally, cigarette smoke, and environmental pollutants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), may play salient roles in female lung carcinogenesis. However, the mechanisms responsible for the interaction of these factors in the promotion of lung cancer are still poorly understood. The present study was designed to explore two ideas: first, the synergistic lung tumorigenic effects of 4-(methylnitrosamino)-1-(3-pyridyl)-butanol (NNK) combined with TCDD, 17ß-estradiol (E2) or both through a long-term treatment experiment, and second, to identify early changes in the inflammatory and signaling pathways through short-term treatment experiments. The results indicate that A/J mice given E2 had strong effects in potentiating NNK-induced activation of MAPK signaling, NFκB, and COX-2 expression. In the long-term exposure model, E2 had a strong tumor promoting effect, whereas TCDD antagonized this effect in A/J mice. We conclude that treatment with NNK combined with either E2 or TCDD induces lung carcinogenesis and the promotion effects could be correlated with lung inflammation. E2 was shown to potentiate NNK-induced inflammation, cell proliferation, thereby leading to lung tumorigenesis.

Synergism between 2,3,7,8-tetrachlorodibenzo-p-dioxin and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone on lung tumor incidence in mice.

Although 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is classified as a human carcinogen, TCDD only induced oxidative DNA damages. In our present study, we combined TCDD with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to investigate their tumorigenic effects on lung tumor formation in A/J mice. Application of NNK at a tumorigenic dose (2 mg/mouse) induced lung adenoma in both male and female A/J mice. Neither application of NNK at a non-tumorigenic dose (1 mg/mouse) nor repeated application of TCDD alone increased tumor incidence. Following the single injection of NNK at a non-tumorigenic dose (1 mg/mouse), repeated application of TCDD significantly increased the lung tumor incidence in female, but not in male, A/J mice 24 weeks later. Utilizing the real-time RT-PCR array, we found that P16 mRNA was significantly reduced in female lung, but not male lung, of NNK/TCDD co-treated A/J mice. With immunohistochemical staining, we confirmed that nuclear P16 protein was reduced in the lungs of NNK/TCDD co-treated female mice. These data suggest that P16 reduction at least partially contributed to synergistic effects of TCDD in lung tumorigenesis.