Pellino-1 confers chemoresistance in lung cancer cells by upregulating cIAP2 through Lys63-mediated polyubiquitination

// Yoon Kyung Jeon 1, * , Chung Kwon Kim 2, * , Jaemoon Koh 1, 3 , Doo Hyun Chung 1, 3 , Geun-Hyoung Ha 2, * 1 Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea 2 Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, Gyeonggi-do, Republic of Korea 3 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea * These authors have contributed equally to this work Correspondence to: Geun-Hyoung Ha, email: hasarang00@skku.edu Yoon Kyung Jeon, email: junarplus@chol.com Keywords: Pellino-1, lung cancer, E3 ligase, oncogene, cIAP2 Received: November 09, 2015     Accepted: May 11, 2016     Published: May 26, 2016 ABSTRACT Pellino-1 is an E3 ubiquitin ligase that mediates immune receptor signaling pathways. The role of Pellino-1 in oncogenesis of lung cancer was investigated in this study. Pellino-1 expression was increased in human lung cancer cell lines compared with non-neoplastic lung cell lines. Pellino-1 overexpression in human lung cancer cells, A549 and H1299 cells, increased the survival and colony forming ability. Pellino-1 overexpression in these cells also conferred resistance to cisplatin- or paclitaxel-induced apoptosis. In contrast, depletion of Pellino-1 decreased the survival of A549 and H1299 cells and sensitized these cells to cisplatin- and paclitaxel-induced apoptosis. Pellino-1 overexpression in A549 and H1299 cells upregulated the expression of inhibitor of apoptosis (IAP) proteins, including cIAP1 and cIAP2, while Pellino-1 depletion downregulated these molecules. Notably, Pellino-1 directly interacted with cIAP2 and stabilized cIAP2 through lysine63-mediated polyubiquitination via its E3 ligase activity. Pellino-1-mediated chemoresistance in lung cancer cells was dependent on the induction of cIAP2. Moreover, a strong positive correlation between Pellino-1 and the cIAP2 expression was observed in human lung adenocarcinoma tissues. Taken together, these results demonstrate that Pellino-1 contributes to lung oncogenesis through the overexpression of cIAP2 and promotion of cell survival and chemoresistance. Pellino-1 might be a novel oncogene and potential therapeutic target in lung cancer.