title: Pellino-1 confers chemoresistance in lung cancer cells by upregulating cIAP2 through Lys63-mediated polyubiquitination.
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.
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Yoon Kyung
authors.initials: YK
authors.lastname: Jeon
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, Gyeonggi-do, Republic of Korea.
authors.forename: Chung Kwon
authors.initials: CK
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Jaemoon
authors.initials: J
authors.lastname: Koh
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
authors.forename: Doo Hyun
authors.initials: DH
authors.lastname: Chung
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, Gyeonggi-do, Republic of Korea.
authors.forename: Geun-Hyoung
authors.initials: GH
authors.lastname: Ha
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D000075747:Baculoviral IAP Repeat-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D025821:Polyubiquitin / Q000378:metabolism*; D034622:RNA Interference; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D009687:Nuclear Proteins; D025821:Polyubiquitin; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; C485959:PELI1 protein, human; D044767:Ubiquitin-Protein Ligases; D008239:Lysine; D017239:Paclitaxel; D002945:Cisplatin
keywords: E3 ligase; Pellino-1; cIAP2; lung cancer; oncogene