title: Cancerous inhibitor of protein phosphatase 2A mediates bortezomib-induced autophagy in hepatocellular carcinoma independent of proteasome.
abstract: 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.
authors: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
authors: Hui-Chuan
authors: HC
authors: Yu
authors: Duen-Ren
authors: DR
authors: Hou
authors: Chun-Yu
authors: CY
authors: Liu
authors: Chen-Si
authors: CS
authors: Lin
authors: Chung-Wai
authors: CW
authors: Shiau
authors: Ann-Lii
authors: AL
authors: Cheng
authors: Kuen-Feng
authors: KF
authors: Chen
mesh_terms: D000165:Acridine Orange; D001324:Autoantigens / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D001897:Boronic Acids / Q000378:metabolism / Q000494:pharmacology*; D000069286:Bortezomib; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008113:Liver Neoplasms / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011719:Pyrazines / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D001324:Autoantigens; D001897:Boronic Acids; C500266:CIP2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011719:Pyrazines; D000069286:Bortezomib; D054648:Protein Phosphatase 2; D046988:Proteasome Endopeptidase Complex; D000165:Acridine Orange
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