Oncotarget

Research Papers:

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

Yoon Kyung Jeon _, Chung Kwon Kim, Jaemoon Koh, Doo Hyun Chung and Geun-Hyoung Ha

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Oncotarget. 2016; 7:41811-41824. https://doi.org/10.18632/oncotarget.9619

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Abstract

Yoon Kyung Jeon1,*, Chung Kwon Kim2,*, Jaemoon Koh1,3, Doo Hyun Chung1,3, Geun-Hyoung Ha2,*

1Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea

2Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 16419, Gyeonggi-do, Republic of Korea

3Department 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.


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