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

Rong Jane Chen, Shih He Siao, Chung Huei Hsu, Chu Yung Chang, Louis W. Chang, Chih Hsiung Wu, Pinpin Lin, Ying Jan Wang

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16 Citations (Scopus)


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 lowdose 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.

Original languageEnglish
Article numbere99586
JournalPLoS ONE
Issue number6
Publication statusPublished - Jun 13 2014

ASJC Scopus subject areas

  • General


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