Cancerous Inhibitor of Protein Phosphatase 2A Mediates Bortezomib-Induced Autophagy in Hepatocellular Carcinoma Independent of Proteasome

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题名:	Cancerous Inhibitor of Protein Phosphatase 2A Mediates Bortezomib-Induced Autophagy in Hepatocellular Carcinoma Independent of Proteasome
作者:	侯敦仁;Yu, Hui-Chuan;Hou, Duen-Ren;Liu, Chun-Yu;Lin, Chen-Si;Shiau, Chung-Wai;Cheng, Ann-Lii;Chen, Kuen-Feng
贡献者:	理學院化學學系
关键词:	Acridine Orange;AKT protein;Apoptosis;Autoantigens - metabolism;Autophagy;Autophagy - drug effects;Biology;Blotting, Western;Boronic Acids - metabolism;Boronic Acids - pharmacology;Bortezomib;Calyculin A;Cancer therapies;Carcinoma, Hepatocellular - metabolism;Cell cycle;Cell death;Cell growth;Cell Line, Tumor;Clinical trials;Dosage and administration;Dose-Response Relationship, Drug;Drug therapy;Ectopic expression;Endoplasmic reticulum;Flow Cytometry;Fluorescent Antibody Technique;Gene Expression Regulation - drug effects;Hepatocellular carcinoma;Humans;Immunoglobulins;Inhibitor drugs;Inhibitors;Kinases;Liver cancer;Liver Neoplasms - metabolism;Medical prognosis;Medical research;Medicine;Membrane Proteins - metabolism;Microscopy, Fluorescence;Phagocytosis;Phosphatase;Phosphatases;Phosphoprotein phosphatase;Phosphorylation;Prostate cancer;Proteasome Endopeptidase Complex - metabolism;Proteasomes;Protein phosphatase;Protein Phosphatase 2 - antagonists & inhibitors;Protein Phosphatase 2 - metabolism;Proteins;Pyrazines - metabolism;Pyrazines - pharmacology;Studies;Targeted cancer therapy;Time Factors;Tumors;Ubiquitin-proteasome system;Veterinary colleges;Veterinary medicine
日期:	2013-02-01
上传时间:	2026-04-21 14:06:18 (UTC+8)
出版者:	Public Library of Science;United States: Public Library of Science (PLoS)
摘要:	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. 其他題名： PLoS One 出版者： United States: Public Library of Science (PLoS) 出版日期： 2013-02-01 出處： PLoS ONE, 2013-02, Vol.8 (2), p.e55705- 資源來源： Agricultural & Environmental Science Collection 版權： COPYRIGHT 2013 Public Library of Science 版權： 2013 Yu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 版權： 2013 Yu et al 2013 Yu et al 識別號： ISSN: 1932-6203 識別號： EISSN: 1932-6203 識別號： DOI: 10.1371/journal.pone.0055705 識別號： PMID: 23383345
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