Alpha 1-antitrypsin activates lung cancer cell survival by acting on cap-dependent protein translation, vesicle-mediated transport, and metastasis

Abstract

Lung cancer remains the leading cause of cancer-related deaths worldwide. Although elevated expression levels of alpha 1-antitrypsin (AAT) have been reported in lung cancer patients, the precise role of AAT in lung cancer progression and prevention has not yet been fully elucidated. We have explored the mechanisms by which AAT stimulates in lung cancer progression. Here, we used proteomic analyses to compare protein levels following AAT overexpression in normal lung L132 cells containing fundamentally low level of AAT. Overexpression of AAT increased levels of proteins involved in transcription and translation, such as signal transducer and activator of transcription 5B (STAT5B) and eukaryotic translation elongation factor 1-alpha 2 (EEF1A2). Furthermore, dual luciferase activity for cap-dependent protein translation increased a 53% at 24 h and 45% at 48 h in AAT-overexpressing cells compared with control. Overexpression of AAT also increased levels of the vesicular transport protein, GOPC, which inhibited the expression of the autophagy protein, BECN1, thereby possibly increasing cell survival. In addition, overexpression of AAT promoted angiogenesis and cell adhesion through increasing expression of the metastatic protein, thrombospondin 1 (THBS1). In contrast, down-regulation of AAT by short hairpin RNA (shRNA) suppressed cell proliferation, metastasis, and adhesion in human lung adenocarcinoma A549 cells and in the lung tissue of K-ras^LA1 lung cancer model mice. These findings strongly suggest that AAT regulation shows promise as an alternative avenue for lung cancer treatment and prevention.