Maximal adamantyl-substituted retinoid-related molecule-induced apoptosis requires NF-κB noncanonical and canonical pathway activation.
Maximal adamantyl-substituted retinoid-related molecule-induced apoptosis requires NF-κB noncanonical and canonical pathway activation.
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DOI：
10.1038/cdd.2010.84
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发表时间：
2011-01
影响因子：
12.4
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中科院分区：
文献类型：
--
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核因子-κB转录因子在调节细胞存活和凋亡中起着关键作用。我们先前已经证明，3-Cl-AHPC是一种被坚决取代的维甲酸类分子，它可以诱导前列腺癌细胞和乳腺癌细胞的凋亡，并需要激活核因子-κB。在这里，我们证明了3-Cl-AHPC激活了人乳腺癌和白血病细胞系中的IKKα和IKKβ，继而激活了规范和非规范的NF-κB通路。3-Cl-AHPC介导的NF-κB典型通路在6h内被激活，而NF-κB非典型通路的最大激活需要48h。敲除小鼠胚胎成纤维细胞中IKKα或IKKβ的表达，以及敲除MDAMB-468细胞中的IKKα或IKKβ，可抑制3-Cl-AHPC介导的细胞凋亡，表明3-Cl-AHPC介导的最大凋亡需要激活正则和非正则途径。在3-Cl-AHPC激活非规范途径之前，半胱氨酸酶介导的E3-连接酶c-IAP1降低，继而稳定了NF-κB诱导激酶(NIK)的表达，TRAF3增加了NIK的结合，激活了IKKα，从而增加了RelB和p52的水平。C-IAP1的表达增加阻断了3-Cl-AHPC介导的NIK水平的稳定和3-Cl-AHPC介导的细胞凋亡。3-Cl-AHPC激活IKKα和IKKβ需要CDC37的表达。这些结果提示，NF-κB通路在3-氯-AHPC介导的细胞凋亡中起重要作用。
NF-κB transcription factors play a critical role in regulating cell survival and apoptosis. We have previously demonstrated that 3-Cl-AHPC, an adamantly substituted retinoid molecule, induced apoptosis and required NF-κB activation in prostate and breast carcinoma cells. Here, we demonstrate that 3-Cl-AHPC activated both IKKα and IKKβ with subsequent activation of the canonical and noncanonical NF-κB pathways in the human breast carcinoma and leukemia cell lines. 3-Cl-AHPC-mediated activation of the NF-κB canonical pathway occurred within 6 h while maximal activation of the NF-κB noncanonical pathway required 48 h. Knockout of IKKα or IKKβ expression in mouse embryonic fibroblast cells and knockdown of IKKα or IKKβ in MDA-MB-468 cells resulted in the inhibition of 3-Cl-AHPC-mediated apoptosis indicating that activation of canonical and noncanonical pathways are required for maximal 3-Cl-AHPC-mediated apoptosis. 3-Cl-AHPC activation of the noncanonical pathway was preceded by caspase-mediated decrease in the E3-ligase c-IAP1 with subsequent stabilization of NF-κB-inducing kinase (NIK) expression, increased binding of NIK by TRAF3, activation of IKKα, and the resultant increased levels of RelB and p52. Increased expression of c-IAP1 blocked 3-Cl-AHPC-mediated stabilization of NIK levels and 3-Cl-AHPC mediated apoptosis. Cdc37 expression was required for activation of IKKα and IKKβ by 3-Cl-AHPC. These findings suggest that NF-κB pathways play an important role in 3-Cl-AHPC mediated apoptosis.
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14.9
作者：
LOMBARDI, L;CIANA, P;NERI, A
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