Does acute phase protein alpha1-antitrypsin modulate apoptosis-autophagy crosstalk resulting in resistance of NSCLC cells to cancer drugs?

Autophagy and apoptosis regulate cell survival and death. Under normal conditions, autophagy is a homeostatic cytoprotective process. However, excessive autophagy is linked to cell death. In cancer, autophagy could rescue cells from drug induced death. Thus, the modulation of autophagy could be important in cancer therapy. We found that the acute phase protein alpha1-antitrypsin (AAT) rescues NSCLC lung cancer cell lines H1975 and H661 from cell death induced by staurosporine (STS), a cytotoxic drug simultaneously activating apoptosis and autophagy. Here, our aim was to analyze in more detail which steps in STS-induced cell death are affected by AAT. In H1975 cells, STS (50 nM) induced caspase-3 activation, reduced Akt/MAPK and mTOR signaling, p62 and FliI levels and increased the LC3B-II to LC3B-I ratio. All STS-induced changes were reversed by AAT (1.5 mg/ml). In presence of STS, AAT stabilized procaspase-3 levels showing for the first time that AAT not only inhibits the activity of executioner caspase-3 but also the step of procaspase-3 activation involving the initiator caspases-8 and -9 in the earlier apoptosis cascade. Interestingly, AAT prevented reduction of p62 levels in STS-treated cells but by itself reduced p62 levels in control cells. Since p62 is a regulator of autophagy and establishes a crosstalk between autophagy and apoptosis, we think that cancer cells may utilize AAT as a pro-survival factor. Probably, under basal conditions AAT induces autophagy as a cyto...
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Lung cancer Source Type: research