Inhibition of protein phosphatase 5 suppresses non-small cell lung cancer through AMP-activated kinase activation
Inhibition of protein phosphatase 5 suppresses non-small cell lung cancer through AMP-activated kinase activation
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DOI：
10.1016/j.lungcan.2017.07.040
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发表时间：
2017-10-01
期刊：
影响因子：
5.3
通讯作者：
Chen, Kuen-Feng
中科院分区：
文献类型：
--
作者：
Hsieh, Feng-Shu;Hung, Man-Hsin;Chen, Kuen-Feng
目的：非小细胞肺癌（NSCLC）仍然是癌症死亡的首要原因。为了改善肺癌的治疗，有必要识别新的癌基因并研究它们在肺癌发生中的作用。蛋白磷酸酶5（PP 5）长期以来被认为调节应激诱导的细胞凋亡和细胞增殖。最近，PP 5已被发现过度表达，并出现作为一个可行的治疗目标，在各种人类癌症，但它在NSCLC中的作用仍然habitu.Materials和方法：PP 5在NSCLC细胞系（A549，H358，和H460）和人类肿瘤样品的表达进行了检查。使用蛋白磷酸酶抑制剂藜芦定和去甲藜芦定作为概念验证化合物来研究PP 5在NSCLC中的病理功能。分析细胞凋亡和细胞信号传导。结果与结论：我们发现PP 5在人肺癌组织中的表达高于癌旁正常组织。PP 5过表达促进A549细胞增殖、集落形成和球体形成能力。抑制PP 5磷酸酶活性的藜芦苷诱导显着的细胞凋亡和上调AMP激活的蛋白激酶（AMPK）信号。重要的是，我们发现PP 5介导的AMPK去磷酸化决定了藜芦苷的体外抗NSCLC作用。与我们的体外数据一致，PP 5抑制抑制H460肿瘤生长并上调肿瘤样品中的p-AMPK。我们的研究结果表明，PP 5抑制通过激活AMPK信号抑制肿瘤生长。靶向致癌PP 5代表了治疗肺癌的有吸引力的治疗策略。
Objectives: Non-small cell lung cancer (NSCLC) continues to be the top cause of cancer death. To improve the treatment of lung cancer, there is necessity to identify novel oncogenes and investigate their effects on lung carcinogenesis. Protein phosphatase 5 (PP5) has long been known to regulate stress-induced apoptosis and cell proliferation. Recently, PP5 has been found overexpressed and emerged as a viable therapeutic target in various human cancers, but its role in NSCLC remains elusive.Materials and methods: The expression of PP5 in NSCLC cell lines (A549, H358, and H460) and human tumor samples were examined. Protein phosphatase inhibitors, cantharidin and norcantharidin, were used as proof-of concept compounds to investigate the pathological function of PP5 in NSCLC. Apoptosis and cellular signaling were analyzed. In vivo efficacy was determined in nude mice with H460 xenograft.Results and conclusion: We found that PP5 was more highly expressed in human lung tumor samples than in adjacent normal tissues. Overexpression of PP5 promoted cell proliferation, colony formation, and sphere forming ability of A549 cells. Inhibition of PP5 phosphatase activity by cantharidin induced significant apoptosis and upregulated AMP-activated protein kinase (AMPK) signaling. Importantly, we found that PP5-mediated dephosphorylation of AMPK determines the in vitro anti-NSCLC effects of cantharidin. Consistent with our in vitro data, PP5 inhibition suppressed H460 tumor growth and upregulated p-AMPK in tumor samples. Our results demonstrate that PP5 inhibition suppresses tumor growth via activating AMPK signaling. Targeting oncogenic PP5 represents an attractive therapeutic strategy for treating lung cancer.