蛋白磷酸酶2A的抑制通过PI3K-AKT途径在胰岛素刺激下使黏液表皮样癌对化疗敏感。
Inhibition of Protein Phosphatase 2A Sensitizes Mucoepidermoid Carcinoma to Chemotherapy via the PI3K-AKT Pathway in Response to Insulin Stimulus.
作者信息
Liu Limin, Wang Herui, Cui Jing, Zhang Qi, Zhang Wei, Xu Wanlin, Lu Hao, Liu Shengwen, Shen Shukun, Fang Francia, Li Lei, Yang Wenjun, Zhuang Zhengping, Li Jiang
机构信息
Department of Oral Pathology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, National Clinical Research Center for Oral Diseases, Shanghai, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China.
Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
出版信息
Cell Physiol Biochem. 2018;50(1):317-331. doi: 10.1159/000494008. Epub 2018 Oct 3.
BACKGROUND/AIMS: Protein phosphatase 2A (PP2A) is a ubiquitous serine/threonine phosphatase that mediates cell cycle regulation and metabolism. Mounting evidence has indicated that PP2A inhibition exhibits considerable anticancer potency in multiple types of human cancers. However, the efficacy of PP2A inhibition remains unexplored in mucoepidermoid carcinoma (MEC), especially in locally advanced and metastatic cases with limited systemic treatment. In this study, we demonstrated the therapeutic potency of LB100 in mucoepidermoid carcinoma.
METHODS
In this study, the expression of PP2A was evaluated using immunohistochemical (IHC) staining. The effects associated with LB100 alone and in combination with cisplatin for the treatment of mucoepidermoid carcinoma were investigated both in vitro, regarding metabolism, proliferation, and migration, and in vivo in a mucoepidermoid carcinoma xenograft model. In addition, with LB100 treatment and in response to an insulin stimulus, the expression levels and phosphorylation levels of targets in the PI3K-AKT pathway were determined using western blot analysis and immunoblotting.
RESULTS
The expression of protein phosphatase 2A was significantly upregulated in the clinical specimens of high-grade MECs compared with those of low-/medium-grade MECs and normal controls. In this article, we report that a small molecule PP2A inhibitor, LB100, decreased cellular viability and glycolytic activity and induced G2/M cell cycle arrest. Importantly, LB100 enhanced the efficacy of cisplatin in mucoepidermoid carcinoma cells both in vitro and in vivo. PP2A inhibition by LB100 increased the phosphorylation of insulin receptor substrate 1(IRS-1) on serine residues, downregulated the expression of phosphatidylinositol 3-kinase (PI3K) p110 alpha subunit and dephosphorylated AKT at Ser473 and Thr308 in mucoepidermoid carcinoma cells in response to insulin stimulus.
CONCLUSION
These results highlight the translational potential of PP2A inhibition to synergize with cisplatin in mucoepidermoid carcinoma treatment.
背景/目的：蛋白磷酸酶2A（PP2A）是一种广泛存在的丝氨酸/苏氨酸磷酸酶，可介导细胞周期调控和代谢。越来越多的证据表明，PP2A抑制在多种类型的人类癌症中显示出相当大的抗癌潜力。然而，PP2A抑制在黏液表皮样癌（MEC）中的疗效尚未得到探索，尤其是在全身治疗有限的局部晚期和转移性病例中。在本研究中，我们证明了LB100在黏液表皮样癌中的治疗潜力。
方法
在本研究中，使用免疫组织化学（IHC）染色评估PP2A的表达。研究了单独使用LB100以及与顺铂联合用于治疗黏液表皮样癌的效果，包括体外的代谢、增殖和迁移，以及在黏液表皮样癌异种移植模型中的体内效果。此外，在LB100治疗并对胰岛素刺激作出反应的情况下，使用蛋白质印迹分析和免疫印迹法测定PI3K-AKT途径中靶点的表达水平和磷酸化水平。
结果
与低/中级别MEC和正常对照的临床标本相比，高级别MEC临床标本中蛋白磷酸酶2A的表达显著上调。在本文中，我们报告一种小分子PP2A抑制剂LB100可降低细胞活力和糖酵解活性，并诱导G2/M期细胞周期阻滞。重要的是，LB100在体外和体内均增强了顺铂对黏液表皮样癌细胞的疗效。LB100对PP2A的抑制增加了胰岛素受体底物1（IRS-1）丝氨酸残基的磷酸化，下调了磷脂酰肌醇3激酶（PI3K）p110α亚基的表达，并使黏液表皮样癌细胞中胰岛素刺激下Ser473和Thr308位点的AKT去磷酸化。
结论
这些结果突出了PP2A抑制在黏液表皮样癌治疗中与顺铂协同作用的转化潜力。
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