The inhibition of lung cancer cell migration by AhR-regulated autophagy

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.

Mesenchymal stem cells promote cell invasion and migration and autophagy‐induced epithelial‐mesenchymal transition in A549 lung adenocarcinoma cells

“…Cellular ROS levels closely associated with the regulation of autophagy, which plays an important role in cancer metastasis by enhancing EMT . Thus, we next examined whether MSC coculture promotes autophagy activation in A549 cells.…”

“…Cellular ROS levels closely associated with the regulation of autophagy, which plays an important role in cancer metastasis by enhancing EMT. 21,22 Thus, we next examined whether MSC coculture promotes autophagy activation in A549 cells. The autophagy response was determined by immunofluorescence staining of autophagic vacuoles, a diagnostic marker of autophagosomes.…”

“…Eventually, a series of autophagy‐related (Atg) protein, such Beclin‐1 (mammalian homologue of Atg6) are elevated and contributed to the maturation of autophagosomes and formation of autolysosomes. Whereas some studies have shown that autophagy could inhibit cancer cell migration and invasion, particularly during the early stages of tumour initiation, as well as suppress EMT by degrading EMT‐associated transcription factors, other studies have shown that autophagy can enhance cancer metastasis via EMT . In colorectal cancer cells, enhancing autophagy is able to increase cell invasion, EMT, and chemotherapy resistance .…”

“…In colorectal cancer cells, enhancing autophagy is able to increase cell invasion, EMT, and chemotherapy resistance . Similarly, aryl hydrocarbon receptor‐mediated autophagy can induce EMT in nonsmall cell lung cancer cells . Nevertheless, it is unclear whether MSCs can promote tumour autophagy for EMT in the tumour microenvironment.…”

“…Whereas some studies have shown that autophagy could inhibit cancer cell migration and invasion, particularly during the early stages of tumour initiation, as well as suppress EMT by degrading EMT-associated transcription factors, [16][17][18][19][20] other studies have shown that autophagy can enhance cancer metastasis via EMT. 21,22 In colorectal cancer cells, enhancing autophagy is able to increase cell invasion, EMT, and chemotherapy resistance. 21 Similarly, aryl hydrocarbon receptor-mediated autophagy can induce EMT in nonsmall cell lung cancer cells.…”