title: Gambogenic acid induces proteasomal degradation of CIP2A and sensitizes hepatocellular carcinoma to anticancer agents.
abstract: Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that is overexpressed in many human malignancies. It regulates phosphorylated AKT and stabilizes c‑Myc in cell proliferation and tumor formation, suggesting that CIP2A plays an essential role in the development of cancer. In the present study, we report that a natural compound, gambogenic acid (GEA), induced the degradation of CIP2A via the ubiquitin‑proteasome pathway. Interestingly, the combination of GEA and proteasome inhibitors potentiated the accumulation of ubiquitinated CIP2A and aggresome formation. In addition, GEA exhibited an inhibitory effect on cell proliferation and CIP2A‑downstream signaling molecules (c‑Myc and pAKT). Furthermore, GEA and CIP2A silencing enhanced the chemosensitivity of hepatocellular carcinoma cells to anticancer agents, suggesting that a combination of a CIP2A inhibitor and anticancer agents could be a valuable clinical therapeutic strategy. These results indicate that GEA is a CIP2A inhibitor that interferes with the ubiquitination and destabilization of CIP2A, providing a promising strategy to enhance the combinational therapy for hepatocellular carcinoma.
authors: Laboratory of Chinese Herbal Pharmacology, Oncology Center, Renmin Hospital and School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China.
authors: Xian-Jun
authors: XJ
authors: Yu
authors: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China.
authors: Qun
authors: Q
authors: Zhao
authors: Laboratory of Chinese Herbal Pharmacology, Oncology Center, Renmin Hospital and School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China.
authors: Xuan-Bin
authors: XB
authors: Wang
authors: Laboratory of Chinese Herbal Pharmacology, Oncology Center, Renmin Hospital and School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China.
authors: Jing-Xuan
authors: JX
authors: Zhang
authors: Center for Translational Medicine, Suizhou Hospital, Hubei University of Medicine, Suizhou, Hubei 441300, P.R. China.
authors: Xiao-Bo
authors: XB
authors: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001324:Autoantigens / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D049109:Cell Proliferation; D004354:Drug Screening Assays, Antitumor; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D054875:Ubiquitination; D014966:Xanthenes / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001324:Autoantigens; C500266:CIP2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D014966:Xanthenes; C045863:neo-gambogic acid; D046988:Proteasome Endopeptidase Complex