期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
卷 1869, 期 9, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.bbamcr.2022.119284
关键词
Transforming growth factor beta (TGF?); Epithelial to mesenchymal transition (EMT); Non-small cell lung cancer (NSCLC); Receptor-mediated endocytosis; Autophagy
资金
- Natural Sciences and Engineering Research Council of Canada [RGPIN-2020-06433]
This study reveals the importance of autophagy in regulating pro-tumorigenic TGF beta signaling. Inhibiting autophagy reduces the activity of the TGF beta signaling pathway, resulting in decreased cell migration and expression of EMT transcription factors. This is associated with decreased internalization of cell surface receptors and their subcellular trafficking.
Transforming growth factor beta (TGF beta) stimulates tumorigenesis by inducing epithelial to mesenchymal transition (EMT) and cell migration. TGF beta signaling is regulated by the endocytosis of cell surface receptors and their subcellular trafficking into the endo-lysosomal system. Here we investigated how autophagy, a cellular quality control network that delivers material to lysosomes, regulates TGF beta signaling pathways that induce EMT and cell migration. We impaired autophagy in non-small cell lung cancer cells using chloroquine, spautin-1, ULK-101, or small interfering RNA (siRNA) targeting autophagy-related gene (ATG)5 and ATG7 and observed that inhibiting autophagy results in a decrease in TGF beta 1-dependent EMT transcription factor and cell marker expression, as well as attenuated stress fiber formation and cell migration. This correlated with decreased internalization of cell surface TGF beta receptors and their trafficking to early/late endosomal and lysosomal compartments. The effects of autophagy inhibition on TGF beta signaling were investigated by Smad2/Smad3 phosphorylation and cellular localization using western blotting, subcellular fractionation, and immunofluorescence microscopy. We observed that inhibiting autophagy decreased the amount and timeframe of Smad2/Smad3 signaling. Taken together, our results suggest that inhibiting autophagy attenuates pro-tumorigenic TGF beta signaling by regulating receptor trafficking, resulting in impaired Smad2/Smad3 phosphorylation and nuclear accumulation.
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