Nazim Uddin Md, Moon Ji-Hong, Lee You-Jin, Seol Jae-Won, Park Sang-Youel
Biosafety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeonbuk 54596, South Korea.
Oncotarget. 2017 Apr 18;8(16):26819-26831. doi: 10.18632/oncotarget.15819.
Members of the tumor necrosis factor (TNF) transmembrane cytokine superfamily, such as TNFα and Fas ligand (FasL), play crucial roles in inflammation and immunity. TRAIL is a member of this superfamily with the ability to selectively trigger cancer cell death but does not motive cytotoxicity to most normal cells. Troglitazone are used in the cure of type II diabetes to reduce blood glucose levels and improve the sensitivity of an amount of tissues to insulin. In this study, we revealed that troglitazone could trigger TRAIL-mediated apoptotic cell death in human lung adenocarcinoma cells. Pretreatment of troglitazone induced activation of PPARγ in a dose-dependent manner. In addition conversion of LC3-I to LC3-II and PPARγ was suppressed in the presence of GW9662, a well-characterized PPARγ antagonist. Treatment with troglitazone resulted in a slight increase in conversion rate of LC3-I to LC3-II and significantly decreased p62 expression levels in a dose-dependent manner. This indicates that troglitazone induced autophagy flux activation in human lung cancer cells. Inhibition of autophagy flux applying a specific inhibitor and genetically modified ATG5 siRNA enclosed troglitazone-mediated enhancing effect of TRAIL. These data demonstrated that activation of PPARγ mediated by troglitazone enhances human lung cancer cells to TRAIL-induced apoptosis via autophagy flux and also suggest that troglitazone may be a combination therapeutic target with TRAIL protein in TRAIL-resistant cancer cells.
肿瘤坏死因子（TNF）跨膜细胞因子超家族的成员，如TNFα和Fas配体（FasL），在炎症和免疫中发挥着关键作用。肿瘤坏死因子相关凋亡诱导配体（TRAIL）是该超家族的成员，具有选择性触发癌细胞死亡的能力，但对大多数正常细胞没有细胞毒性。曲格列酮用于治疗II型糖尿病，以降低血糖水平并提高一些组织对胰岛素的敏感性。在本研究中，我们发现曲格列酮可触发人肺腺癌细胞中TRAIL介导的凋亡细胞死亡。曲格列酮预处理以剂量依赖性方式诱导过氧化物酶体增殖物激活受体γ（PPARγ）的激活。此外，在存在已充分表征的PPARγ拮抗剂GW9662的情况下，LC3-I向LC3-II的转化以及PPARγ受到抑制。用曲格列酮处理导致LC3-I向LC3-II的转化率略有增加，并以剂量依赖性方式显著降低p62表达水平。这表明曲格列酮诱导人肺癌细胞中的自噬流激活。应用特异性抑制剂和基因修饰的自噬相关蛋白5（ATG5）小干扰RNA抑制自噬流可增强曲格列酮介导的TRAIL效应。这些数据表明，曲格列酮介导的PPARγ激活通过自噬流增强人肺癌细胞对TRAIL诱导的凋亡的敏感性，并且还表明曲格列酮可能是TRAIL耐药癌细胞中与TRAIL蛋白联合治疗的靶点。
