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.
Highlights
Pellino family proteins (Pellino-1, 2, and 3) are E3 ubiquitin ligases that contains C-terminal RINGlike domains [1]
These results demonstrate that Pellino-1 contributes to lung oncogenesis through the overexpression of cIAP2 and promotion of cell survival and chemoresistance
Pellino-1 is variably expressed in lung cancer cell lines and associated with toll-like receptors (TLRs) expression
Summary
Pellino family proteins (Pellino-1, 2, and 3) are E3 ubiquitin ligases that contains C-terminal RINGlike domains [1]. Pellino proteins play an important role in Toll-like receptor (TLR), IL-1 receptor and T-cell receptor (TCR) signaling, by catalyzing Lys48- and Lys63-linked polyubiquitination of signaling molecules [2]. Pellino-1 functions as a critical mediator for NF-κB activation in TLR3 and TLR4 signaling through its Lys63-linked ubiquitin ligase activity [3]. Pellino-1 is implicated in MyD88-mediated TLR signaling and subsequent MAPK, ERK, and JNK activation [4, 5]. Pellino-1 positively regulates type I interferon responses in human bronchial epithelial cells after TLR3 stimulation or rhinovirus infection [6]. Pellino-1 acts as a negative regulator of TCR signaling by promoting Lys48-linked polyubiquitination and proteasomal degradation of REL, an NF-κB subunit [7]. The expression of Pellino-1 increases following the TLR or TCR signaling [8]
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