https://scholars.lib.ntu.edu.tw/handle/123456789/580218
標題: | Cancerous Inhibitor of Protein Phosphatase 2A Mediates Bortezomib-Induced Autophagy in Hepatocellular Carcinoma Independent of Proteasome | 作者: | Yu H.-C. Hou D.-R. Liu C.-Y. Lin C.-S. Shiau C.-W. ANN-LII CHENG Chen K.-F. |
公開日期: | 2013 | 卷: | 8 | 期: | 2 | 來源出版物: | PLoS ONE | 摘要: | Previously, we reported that cancerous inhibitor of protein phosphatase 2A (CIP2A) mediates the apoptotic effect of bortezomib in hepatocellular carcinoma (HCC). Here, we report a proteasome-independent mechanism by which bortezomib induces autophagy in HCC. Our data indicate that bortezomib activated autophagy in a dose- and time- dependent manner in HCC cell lines including Huh-7, Sk-Hep1, and Hep3B. Bortezomib downregulated CIP2A, phospho-Akt (P-Akt) and phospho-4EBP1 (P-4EBP1) in a dose- and time-dependent manner in all tested HCC cells. Ectopic expression of CIP2A abolished the effect of bortezomib on autophagy. Co-treatment of bortezomib and calyculin A, a PP2A inhibitor, reduced the effect of bortezomib on P-Akt, P-4EBP1, and autophagy. Increased phosphorylation of either Akt or 4EBP1 by ectopic overexpression protected cells from bortezomib-induced autophagy. Furthermore, we examined the effect of ΔBtz, a bortezomib derivative that closely resembles bortezomib structurally but has no proteasome activity, in HCC. Interestingly, ΔBtz demonstrated similar effects to bortezomib on autophagy, CIP2A, P-Akt and P-4EBP1, suggesting that the effect of bortezomib on autophagy is independent of proteasome inhibition. Moreover, our in vivo data showed that both bortezomib and ΔBtz inhibited tumor growth, downregulated CIP2A, P-Akt and induced autophagy in Huh-7 tumors. In conclusion, bortezomib induces autophagy in HCC through a CIP2A-PP2A-Akt-4EBP1 pathway. ? 2013 Yu et al. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84873273329&doi=10.1371%2fjournal.pone.0055705&partnerID=40&md5=c1384a3f7d576654dbcdf07b576536e6 https://scholars.lib.ntu.edu.tw/handle/123456789/580218 |
DOI: | 10.1371/journal.pone.0055705 | SDG/關鍵字: | bortezomib; calyculin A; cancerous inhibitor of protein phosphatase 2A; initiation factor 4E binding protein 1; phosphoprotein phosphatase; phosphoprotein phosphatase 2A; proteasome; protein kinase B; unclassified drug; animal experiment; animal model; article; autophagy; cancer cell culture; cancer inhibition; controlled study; dose time effect relation; down regulation; drug effect; drug mechanism; drug structure; human; human cell; in vivo study; liver cell carcinoma; male; mouse; nonhuman; outcome assessment; protein expression; protein phosphorylation; tumor xenograft; Acridine Orange; Autoantigens; Autophagy; Blotting, Western; Boronic Acids; Carcinoma, Hepatocellular; Cell Line, Tumor; Dose-Response Relationship, Drug; Flow Cytometry; Fluorescent Antibody Technique; Gene Expression Regulation; Humans; Liver Neoplasms; Membrane Proteins; Microscopy, Fluorescence; Phosphorylation; Proteasome Endopeptidase Complex; Protein Phosphatase 2; Pyrazines; Time Factors |
顯示於: | 醫學系 |
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