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.

Identification of MTHFD2 as a novel prognosis biomarker in esophageal carcinoma patients based on transcriptomic data and methylation profiling

“…[ 49 ] Furthermore, PELI1 promotes cell survival and chemoresistance by upregulating the expression of cIAP2 in lung cancer. [ 50 ] Taken together, these findings suggest that PELI1 might be a potential therapeutic target in some tumor types.…”

α-amanitin resistance in Drosophila melanogaster: A genome-wide association approach

“…The Pellino protein regulates the Toll/Toll-like pathways, which respond to microbial antigens [ 47 – 49 ]. Interestingly, human Pellino-1 has been shown to confer resistance to two chemotherapeutic drugs in lung cancer cells [ 50 ]. Although it is not entirely clear how an innate immune pathway might lead to α-amanitin resistance in fruit flies, the innate immune system is capable of identifying and removing foreign substances from the body, and links between the innate immunity and autophagy have been described earlier [ 51 , 52 ].…”

A perspective profile of ADCY1 in cAMP signaling with drug-resistance in lung cancer

“…The cAMP-response-element-binding protein (CREB) can also regulate the activity of IAPs through the regulation of the enhancer sequence of IAPs to control cell apoptosis and DNA damage processes 55. The overexpression of IAP2 could enhance chemotherapy resistance and promote cell survival in lung cancer cells 56.…”

“…The X-ray repair cross-complementing protein 1 (XRCC1) can affect cellular sensitivity to ionizing radiation. The expression and polymorphisms of XRCC1 play an important role in DNA repair and it may be a prognosis biomarker for lung cancer patients treated with radiation or chemotherapy 57. The cAMP signaling pathway can regulate DNA repair and hence contribute to radiation and chemotherapy resistance by inhibiting the expression of XRCC1in lung cancer patients 58.…”