https://scholars.lib.ntu.edu.tw/handle/123456789/361201
標題: | FOXO3a-dependent mechanism of E1A-induced chemosensitization | 作者: | Su, J.-L Cheng, X Yamaguchi, H Chang, Y.-W Hou, C.-F Lee, D.-F Ko, H.-W KUO-TAI HUA Wang, Y.-N Hsiao, M Chen, P.B Hsu, J.-M Bast Jr., R.C Hortobagyi, G.N Hung, M.-C. |
公開日期: | 2011 | 卷: | 71 | 期: | 21 | 起(迄)頁: | 6878-6887 | 來源出版物: | Cancer Research | 摘要: | Gene therapy trials in human breast, ovarian, and head and neck tumors indicate that adenovirus E1A can sensitize cancer cells to the cytotoxic effects of paclitaxel in vitro and in vivo. Resistance to paclitaxel has been reported to occur in cells expressing lowlevels of the Forkhead transcription factor FOXO3a. In this article, wereport that FOXO3a is critical for E1A-mediated chemosensitization to paclitaxel. RNAinterference-mediated knockdown of FOXO3a abolished E1A-induced sensitivity to paclitaxel. Mechanistic investigations indicated that E1A indirectly stabilized FOXO3a by acting at an intermediate step to inhibit a ubiquitin-dependent proteolysis pathway involving the E3 ligase βTrCP and the FOXO3a inhibitory kinase IKKβ. E1Aderepressed this inhibitory pathway by stimulating expression of the protein phosphatase 2A (PP2A)/C protein phosphatases,which by binding to the TGF-β-activated kinase TAK1, inhibited its ability to activate IKKβ and, thereby, to suppress βTrCP-mediated degradation of FOXO3a. Thus, by stimulating PP2A/C expression, E1A triggers a signaling cascade that stabilizes FOXO3a and mediates chemosensitization. Our findings provide a leap forward in understanding paclitaxel chemosensitization by E1A, and offer a mechanistic rational to apply E1A gene therapy as an adjuvant for improving therapeutic outcomes in patients receiving paclitaxel treatment. ?2011 AACR. |
URI: | http://www.scopus.com/inward/record.url?eid=2-s2.0-80155126631&partnerID=MN8TOARS http://scholars.lib.ntu.edu.tw/handle/123456789/361201 |
DOI: | 10.1158/0008-5472.CAN-11-0295 | SDG/關鍵字: | C protein phosphatase; E1A protein; I kappa B kinase beta; paclitaxel; phosphatase; phosphoprotein phosphatase 2A; protein beta TrCP; transcription factor FKHRL1; transforming growth factor beta; transforming growth factor beta activated kinase 1; ubiquitin; ubiquitin protein ligase E3; unclassified drug; animal experiment; animal model; animal tissue; article; breast tumor; controlled study; drug sensitization; enzyme activation; female; gene silencing; human; human cell; mouse; nonhuman; priority journal; protein binding; protein degradation; protein expression; protein function; protein stability; RNA interference; signal transduction; Adenocarcinoma; Adenovirus E1A Proteins; Adenoviruses, Human; Animals; Antibodies, Monoclonal; beta-Transducin Repeat-Containing Proteins; Breast Neoplasms; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Forkhead Transcription Factors; Gene Therapy; Genetic Vectors; Humans; I-kappa B Kinase; MAP Kinase Kinase Kinases; Mice; Mice, SCID; Neoplasm Proteins; Paclitaxel; Protein Phosphatase 2; Protein Stability; RNA, Small Interfering; Signal Transduction; Ubiquitin; Xenograft Model Antitumor Assays |
顯示於: | 毒理學研究所 |
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