Yao J, Duan L, Fan M, Yuan J, Wu X
Institute of Virology, School of Medicine, Wuhan University, Wuhan, Hubei, People's Republic of China.
Int J Gynecol Cancer. 2007 Mar-Apr;17(2):502-10. doi: 10.1111/j.1525-1438.2007.00872.x. Epub 2007 Feb 19.
Notch signaling can serve as a tumor suppressor or tumor promoter in the same kind of cancer, such as human papillomavirus-positive cervical cancer cells. However, the exact mechanisms remain poorly characterized. Our studies demonstrated that constitutively overexpressed active Notch1 via stable transfection with exogenous intracellular domain of Notch1 (ICN) resulted in growth inhibition of the human cervical cancer cell line HeLa by inducing G(2)-M arrest and apoptosis. Moreover, the growth inhibition was correlated with inhibition of nuclear factor kappa B (NF-kappaB) p50 activation, accompanied by a decrease in the nuclear expression of NF-kappaB p50 and an increase in the cytosolic expression of IkappaBalpha. Consistent with these results, downregulation of cyclin D1 and Bcl-2, which are both the downstream genes of NF-kappaB, were observed in ICN-overexpressed cells. Overall, our results suggest that NF-kappaB inhibition may contribute partially to cell cycle arrest and apoptosis induced by Notch1 activation in human cervical cancer cells.
Notch信号在同一种癌症中既可以作为肿瘤抑制因子，也可以作为肿瘤促进因子，比如在人乳头瘤病毒阳性的宫颈癌细胞中。然而，其确切机制仍不清楚。我们的研究表明，通过稳定转染Notch1的细胞内结构域（ICN）使活性Notch1持续过表达，可通过诱导G(2)-M期阻滞和凋亡来抑制人宫颈癌细胞系HeLa的生长。此外，生长抑制与核因子κB（NF-κB）p50激活的抑制相关，同时伴有NF-κB p50核表达的降低和IκBα胞质表达的增加。与这些结果一致，在ICN过表达的细胞中观察到细胞周期蛋白D1和Bcl-2（二者均为NF-κB的下游基因）的下调。总体而言，我们的结果表明，NF-κB抑制可能部分导致了Notch1激活诱导的人宫颈癌细胞的细胞周期阻滞和凋亡。
