Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is highly expressed in multiple organs and tissues. Whereas AhR mediates the metabolism of xenobiotic and endogenous compounds, its novel function in cancer epithelial-mesenchymal transition (EMT) remains controversial. Autophagy also participates in tumour progression through its functions in cell homeostasis and facilitates adaptation to EMT progression. In the present study, we found that AhR-regulated autophagy positively modulates EMT in non-small cell lung cancer cells. The motility of A549, H1299, and CL1-5 cells were correlated with different AhR expression levels. Invasive potential and cell morphology also changed when AhR protein expression was altered. Moreover, AhR levels exerted a contrasting effect on autophagy potential. Autophagy was higher in CL1-5 and H1299 cells with lower AhR levels than in A549 cells. Both AhR overexpression and autophagy inhibition decreased CL1-5 metastasis in vivo. Furthermore, AhR promoted BNIP3 ubiquitination for proteasomal degradation. AhR silencing in A549 cells also reduced BNIP3 ubiquitination. Taken together, these results provide a novel insight into the cross-linking between AhR and autophagy, we addressed the mechanistic BNIP3 modulation by endogenous AhR, which affect cancer cell EMT progression.
Highlights
Lung cancer is a widespread cancer with a high mortality rate in both men and women[1] and contributes to more than one-quarter of the total cancer-related deaths worldwide
The results showed that A549 cells, which express high levels of aryl hydrocarbon receptor (AhR), exhibited lower cell migration ability along with high E-cadherin and low vimentin expression
We confirmed the differences in cell invasive potential between non-small cell lung cancer (NSCLC) cells; after comparing the protein expression levels of AhR, A549 and CL1-5 cells were selected for subsequent experiments (Fig. S1)
Summary
Lung cancer is a widespread cancer with a high mortality rate in both men and women[1] and contributes to more than one-quarter of the total cancer-related deaths worldwide. Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous components present in cigarette smoke and air pollution, and are considered to be the most important carcinogens in these complex mixtures[5] Chemicals such as PAHs exert direct biological effects by binding to AhR, a ligand-activated receptor. An increasing number of studies indicates that AhR plays a novel role in cell migration, proliferation, and chronic inflammation in carcinogenesis[9,10] Both tumour-suppressor and pro-oncogenic functions have been reported for AhR in different cancers, the relationship between AhR and cancer metastasis remains unclear. We sought to elucidate the exact signalling pathway involved in AhR-regulated autophagy and EMT, the novel crosstalk to determine how AhR levels affect lung cancer metastasis
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