N-acetylcysteine negatively regulates Notch3 and its malignant signaling.
N-acetylcysteine negatively regulates Notch3 and its malignant signaling.
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N-乙酰半胱氨酸负向调节Notch3及其恶性信号传导
DOI：
10.18632/oncotarget.8806
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发表时间：
2016-05-24
期刊：
影响因子：
--
通讯作者：
Zhu JH
中科院分区：
文献类型：
--
作者：
Zhang X;Wang YN;Zhu JJ;Liu XX;You H;Gong MY;Zou M;Cheng WH;Zhu JH
NOTCH3受体在多种肿瘤中都有表达，被切除的活性胞内区(N3ICD)启动了它的信号级联反应。N-乙酰半胱氨酸(NAC)作为一种抗氧化剂，已被用于癌症的预防和治疗。在这项研究中，我们证明了NAC对癌细胞中Notch3的负调控。经NAC处理的HeLa细胞中，Notch3及其下游效应因子Hes1和HRT1的水平呈时间和浓度依赖性的下降，这种下降不依赖于f-分泌酶或谷胱甘肽。相反，NAC不影响Notch1(全长Notch3前体)的蛋白水平，也不影响N3ICD的异位表达。虽然超氧化物歧化酶、过氧化氢酶和NAC抑制HeLa细胞中的活性氧，但前两种抗氧化剂对Notch3水平没有影响。而NAC不改变Notch3的mRNA表达，但对溶酶体的功能性抑制可阻断NAC依赖的Notch3水平的降低。此外，Notch3沉默和N3ICD过表达的结果表明，NAC通过下调多种癌细胞中的Notch3蛋白来阻止恶性表型。综上所述，NAC通过溶酶体依赖的蛋白质降解降低Notch3的水平，从而负面调节癌细胞中的Notch3恶性信号。这些结果暗示了一种新的NAC治疗方法，用于增敏Notch3表达的肿瘤。
Notch3 receptor is expressed in a variety of cancers and the excised active intracellular domain (N3ICD) initiates its signaling cascade. N-acetylcysteine (NAC) as an antioxidant has been implicated in cancer prevention and therapy. In this study, we demonstrated a negative regulation of Notch3 by NAC in cancer cells. HeLa cells treated with NAC exhibited a time- and concentration-dependent decrease in Notch3 levels and its downstream effectors Hes1 and HRT1 in a manner independent of f-secretase or glutathione. In contrast, NAC did not affect protein levels of Notch1, the full length Notch3 precursor, or ectopically expressed N3ICD. Although SOD, catalase and NAC suppressed reactive oxygen species in HeLa cells, the first two antioxidants did not impact on Notch3 levels. While the mRNA expression of Notch3 was not altered by NAC, functional inhibition of lysosome, but not proteasome, blocked the NAC-dependent reduction of Notch3 levels. Furthermore, results from Notch3 silencing and N3ICD overexpression demonstrated that NAC prevented malignant phenotypes through down-regulation of Notch3 protein in multiple cancer cells. In summary, NAC reduces Notch3 levels through lysosome-dependent protein degradation, thereby negatively regulates Notch3 malignant signaling in cancer cells. These results implicate a novel NAC treatment in sensitizing Notch3-expressing tumors.
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影响因子：
3.7
作者：
Gordon WR;Vardar-Ulu D;L'Heureux S;Ashworth T;Malecki MJ;Sanchez-Irizarry C;McArthur DG;Histen G;Mitchell JL;Aster JC;Blacklow SC
通讯作者：
Blacklow SC
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4.8
作者：
Lee, Ming-Fen;Chan, Chien-Yi;Huang, Chun-Yin
通讯作者：
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影响因子：
8
作者：
Curry, CL;Reed, LL;Foreman, KE
通讯作者：
Foreman, KE
影响因子：
5.9
作者：
FLANAGAN, RJ;MEREDITH, TJ
通讯作者：
MEREDITH, TJ
影响因子：
7.4
作者：
ARUOMA, OI;HALLIWELL, B;BUTLER, J
通讯作者：
BUTLER, J