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

// Seung-Hee Chang 1, * , Kyung-Cho Cho 2, * , Kyeong-Nam Yu 1 , Seong-Ho Hong 1 , Sungjin Park 1 , Ah Young Lee 1 , Sanghwa Kim 1, 3 , Somin Lee 1, 3 , Jeong Won Kang 2 , Chanhee Chae 4 , Jongsun Park 5 , Kwang Pyo Kim 2 , Myung-Haing Cho 1, 3, 6, 7, 8 1 Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea 2 Department of Applied Chemistry, College of Applied Science, Kyung Hee University, Yongin 463-707, Korea 3 Graduate Group of Tumor Biology, Seoul National University, Seoul 110-799, Korea 4 Laboratory of Pathology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea 5 Department of Pharmacology and Medical Science, Metabolic Diseases and Cell Signaling Laboratory, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-747, Korea 6 Graduate School of Convergence Science and Technology, Seoul National University, Suwon 443-270, Korea 7 Advanced Institutes of Convergence Technology, Seoul National University, Suwon 443-270, Korea 8 Institute of GreenBio Science Technology, Seoul National University, Pyeongchang-gun, Gangwon-do 232-916, Korea * These authors have contributed equally to this work Correspondence to: Kwang Pyo Kim, email: kimkp@khu.ac.kr Myung-Haing Cho, email: mchotox@snu.ac.kr Keywords: alpha 1-antitrypsin (AAT), cap-dependent translation, thrombospondin1 (THBS1), cell adhesion molecule (CAM), lung cancer Received: October 26, 2015 Accepted: June 12, 2016 Published: July 19, 2016 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.