Endoplasmic reticulum-Golgi intermediate compartment protein 3 knockdown suppresses lung cancer through endoplasmic reticulum stress-induced autophagy

// Seong-Ho Hong 1, 2 , Seung-Hee Chang 1 , Kyung-Cho Cho 3 , Sanghwa Kim 1, 4 , Sungjin Park 1 , Ah Young Lee 1 , Hu-Lin Jiang 5 , Hyeon-Jeong Kim 1 , Somin Lee 1, 4 , Kyeong-Nam Yu 1 , Hwi Won Seo 6 , Chanhee Chae 6 , Kwang Pyo Kim 3 , Jongsun Park 7 , Myung-Haing Cho 1, 4, 8, 9, 10 1 Laboratory of Toxicology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea 2 New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea 3 Department of Applied Chemistry, College of Applied Science, Kyung Hee University, Yongin 17104, Korea 4 Graduate Group of Tumor Biology, Seoul National University, Seoul 08826, Korea 5 Department of Pharmaceutics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China 6 Laboratory of Pathology, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea 7 Department of Pharmacology and Medical Science, Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon 35015, Korea 8 Graduate School of Convergence Science and Technology, Seoul National University, Suwon 16229, Korea 9 Advanced Institute of Convergence Technology, Seoul National University, Suwon 16229, Korea 10 Institute of GreenBio Science Technology, Seoul National University, Pyeongchang-gun 25354, Korea Correspondence to: Myung-Haing Cho, email: mchotox@snu.ac.kr Jongsun Park, email: insulin@cnu.ac.kr Keywords: lung cancer, gene therapy, endoplasmic reticulum-Golgi intermediate compartment protein 3 (ERGIC3), golgi apparatus, ER stress Received: February 01, 2016 Accepted: August 08, 2016 Published: August 29, 2016 ABSTRACT Trafficking from the endoplasmic reticulum (ER) to the Golgi apparatus is elevated in cancer cells. Therefore, proteins of the ER-Golgi intermediate compartment (ERGIC) attract significant attention as targets for cancer treatment. Enhanced cancer cell growth and epithelial-mesenchymal transition by ERGICs correlates with poor-prognosis of lung cancer. This prompted us to assess whether knockdown of ERGIC3 may decrease lung cancer growth. To test the hypothesis, the effects of ERGIC3 short hairpin RNA (shERGIC3) on ER stress-induced cell death and lung tumorigenesis were investigated both in vitro and in vivo . Knockdown of ERGIC3 led to ER stress-induced autophagic cell death and suppression of proliferation in the A549 human lung cancer cell-line. Moreover, non-invasive aerosol-delivery of shERGIC3 using the biocompatible carrier glycerol propoxylate triacrylate and spermine (GPT-SPE) inhibited lung tumorigenesis in the K-ras LA1 murine model of lung cancer. Our data suggest that suppression of ERGIC3 could provide a framework for the development of effective lung cancer therapies.