Abstract
Abstract Background: JAB1 (c-Jun activation domain binding protein-1) is a c-Jun coactivator, also known as COP9 signalosome subunit 5 (CSN5). Jab1 has an important role in cell proliferation and apoptosis. Overexpression of Jab1 is correlated with poor prognosis in various cancers. Biliary tract cancer (BTC) has a poor prognosis with a huge unmet medical need. The role of Jab1 has not been studied in BTC. We investigated the role and mechanism of Jab1 as a potential therapeutic target in BTC. Methods: We used 8 kinds of BTC cells and designed Jab1 siRNA. MTT assay and colony formation assay were done to determine growth inhibitory effect of Jab1 knockdown. Cell cycle analysis was done by FACS Calibur flow cytometer and cell migration was evaluated by wound healing assay. We used cycloheximide chase assay for measuring of protein half-life. Results: BTC cell lines showed high level of Jab1 expression. Among them, SNU478, SNU869 and SNU 1196 were indicated with especially higher level of Jab1 expression. Cell growth and proliferation of BTC cells were decreased by Jab1 knockdown. Depletion of Jab1 induced G1 arrest, as well as decreased CyclinD/CyclinA and increased p27. Cell migration was also inhibited by Jab1 knockdown. Inhibition of Jab1 showed the decrease of pSrc, pAkt. Interestingly, depletion of Jab1 led to the elevation of PTEN protein levels without change of PTEN mRNA levels. PTEN half-life was longer in Jab1 siRNA-transfected cells. Suppression of Jab1 increased the sensitivity of BTC cells to the cytotoxic chemotherapeutic agent. Conclusion: Suppression of Jab1 shows antitumor effects in BTC cells by inhibiting cell proliferation, migration, cell cycle and increase of chemosensitivity. Taken together, Jab1 might be a potential therapeutic target in BTC. Citation Format: Ah-Rong Nam, Kyo Hwa Kang, Ji Eun Park, Ju-Hee Bang, Ling Jin, Mei Hua Jin, Tae Yong Kim, Sae-Won Han, Sang-Hyun Song, Seock-Ah Im, Tae-You Kim, Do-Youn Oh, Yung-Jue Bang. The role and mechanism of JAB1 as a therapeutic target in biliary tract cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1714. doi:10.1158/1538-7445.AM2015-1714
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