Yu Xian-Jun, Zhao Qun, Wang Xuan-Bin, Zhang Jing-Xuan, Wang Xiao-Bo
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.
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.
Oncol Rep. 2016 Dec;36(6):3611-3618. doi: 10.3892/or.2016.5188. Epub 2016 Oct 20.
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.
蛋白磷酸酶2A的癌性抑制剂（CIP2A）是一种癌蛋白，在许多人类恶性肿瘤中过表达。它在细胞增殖和肿瘤形成过程中调节磷酸化的AKT并稳定c-Myc，这表明CIP2A在癌症发展中起重要作用。在本研究中，我们报道一种天然化合物藤黄酸（GEA）通过泛素-蛋白酶体途径诱导CIP2A降解。有趣的是，GEA与蛋白酶体抑制剂的组合增强了泛素化CIP2A的积累和聚集体形成。此外，GEA对细胞增殖和CIP2A下游信号分子（c-Myc和pAKT）表现出抑制作用。此外，GEA和CIP2A沉默增强了肝癌细胞对抗癌药物的化学敏感性，这表明CIP2A抑制剂与抗癌药物的联合可能是一种有价值的临床治疗策略。这些结果表明，GEA是一种CIP2A抑制剂，可干扰CIP2A的泛素化和稳定性，为增强肝癌联合治疗提供了一种有前景的策略。
