Huang Ya-Chun, Yu Hsin-Su, Chai Chee-Yin
Department of Pathology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
Toxicol Lett. 2015 Dec 15;239(3):172-81. doi: 10.1016/j.toxlet.2015.09.022. Epub 2015 Sep 30.
Studies show that arsenite induces oxidative stress and modifies cellular function via phosphorylation of proteins and inhibition of DNA repair enzymes. Autophagy, which has multiple physiological and pathological roles in cellular function, is initiated by oxidative stress and is regulated by the signaling pathways of phosphatidylinositol 3-phosphate kinase (PI3K)/mammalian target of rapamycin (mTOR)/p70S6 kinase (p70S6K) and extracellular signaling-regulated protein kinase 1/2 (ERK1/2) that play important roles in oncogenesis. However, the effects of arsenite-induced oxidative stress on autophagy and on expression of related proteins are not fully understood. This study found that cells treated with sodium arsenite had reduced 8-oxoguanine DNA glycosylase 1 (OGG1) and increased 8-hydroxy-2'-deoxyguanosine (8-OHdG) and activating transcription factor (ATF) 3 in SV-40 immortalized human uroepithelial (SV-HUC-1) cells. Arsenite also increased the number of autophagosomes and increased levels of the autophagy markers Beclin-1 and microtubule-associated protein 1 light chain 3B. Reactive oxygen species scavenger decreased arsenite-induced autophagy in SV-HUC-1 cells. Our previous work showed that arsenite induced phosphorylation of the ERK1/2 signaling pathway. The current study further showed that arsenite decreased phosphatase and tensin homologue (PTEN) levels and increased phospho-p70S6 kinase (p-p70S6K) in SV-HUC-1 cells. However, both kinase inhibitor U0126 and the DNA (cytosine-5-)-methyltransferase 1 (DNMT1) inhibitor 5-aza-deoxycytidine abolished the effect of arsenite on expressions of PTEN and p-p70S6K. These results show that autophagy induced by arsenite exposure is mediated by oxidative stress, which regulates activation of the PTEN, p70S6K and ERK1/2 signaling pathways. Thus, this study clarifies the role of autophagy in arsenite-induced urothelial carcinogenesis.
研究表明，亚砷酸盐可诱导氧化应激，并通过蛋白质磷酸化和抑制DNA修复酶来改变细胞功能。自噬在细胞功能中具有多种生理和病理作用，由氧化应激引发，并受磷脂酰肌醇3-磷酸激酶（PI3K）/哺乳动物雷帕霉素靶蛋白（mTOR）/p70核糖体蛋白S6激酶（p70S6K）以及在肿瘤发生中起重要作用的细胞外信号调节蛋白激酶1/2（ERK1/2）的信号通路调控。然而，亚砷酸盐诱导的氧化应激对自噬及相关蛋白表达的影响尚未完全明确。本研究发现，用亚砷酸钠处理的细胞中，SV-40永生化人尿路上皮（SV-HUC-1）细胞中的8-氧代鸟嘌呤DNA糖基化酶1（OGG1）减少，8-羟基-2'-脱氧鸟苷（8-OHdG）和激活转录因子（ATF）3增加。亚砷酸盐还增加了自噬体的数量，并提高了自噬标志物Beclin-1和微管相关蛋白1轻链3B的水平。活性氧清除剂可降低亚砷酸盐诱导的SV-HUC-1细胞自噬。我们之前的研究表明，亚砷酸盐可诱导ERK1/2信号通路的磷酸化。本研究进一步表明，亚砷酸盐可降低SV-HUC-1细胞中磷酸酶和张力蛋白同源物（PTEN）的水平，并增加磷酸化p70S6激酶（p-p70S6K）的水平。然而，激酶抑制剂U0126和DNA（胞嘧啶-5-）-甲基转移酶1（DNMT1）抑制剂5-氮杂-脱氧胞苷均消除了亚砷酸盐对PTEN和p-p70S6K表达的影响。这些结果表明，亚砷酸盐暴露诱导的自噬由氧化应激介导，氧化应激调节PTEN、p70S6K和ERK1/2信号通路的激活。因此，本研究阐明了自噬在亚砷酸盐诱导的尿路上皮癌发生中的作用。
