Astaxanthin inhibits NF-κB and Wnt/β-catenin signaling pathways via inactivation of Erk/MAPK and PI3K/Akt to induce intrinsic apoptosis in a hamster model of oral cancer
Astaxanthin inhibits NF-κB and Wnt/β-catenin signaling pathways via inactivation of Erk/MAPK and PI3K/Akt to induce intrinsic apoptosis in a hamster model of oral cancer
复制标题
DOI：
10.1016/j.bbagen.2013.05.032
复制
发表时间：
2013-10-01
影响因子：
3
通讯作者：
Nagini, S.
中科院分区：
文献类型：
--
作者：
Kavitha, K.;Kowshik, J.;Nagini, S.
背景：由上游丝氨酸/苏氨酸激酶激活的致癌转录因子核因子-kappaB和β-连环蛋白控制着包括细胞凋亡逃避在内的多种细胞恶性转化过程。本研究旨在探讨抗氧化剂类胡萝卜素虾青素对金黄地鼠颊囊(HBP)癌变模型的化学预防作用。方法：采用实时定量RT-PCR、免疫印迹、免疫印迹等方法，研究了虾青素对金黄地鼠颊囊(HBP)致癌过程中核因子-kappaB、Wnt/β-catenin、上游激活蛋白ERK/MAPK、PI-3K/Akt及下游事件-细胞凋亡逃避的影响。结果：我们发现虾青素通过下调关键调控酶IKKβ和GSK-3β来抑制NF-kappaB和Wnt信号转导。对基因表达和对接相互作用的分析表明，这些途径的抑制可能是通过虾青素失活上游信号通路Erk/Akt来实现的。虾青素还通过下调抗凋亡基因Bcl2、p-Bad和Survivin的表达，上调促凋亡基因Bax和Bad的表达，并伴随Smac/Diablo和细胞色素-c的外流，诱导多聚ADP核糖聚合酶(PARP)的裂解，从而诱导caspase介导的线粒体凋亡。结论：虾青素通过抑制转录因子和信号通路的磷酸化，诱导内源性细胞凋亡而发挥化学预防作用。(C)2013爱思唯尔B.V.保留所有权利。
Background: The oncogenic transcription factors NF-kappa B and beta-catenin, constitutively activated by upstream serine/threonine kinases control several cellular processes implicated in malignant transformation including apoptosis evasion. The aim of this study was to investigate the chemopreventive effects of astaxanthin, an antioxidant carotenoid, in the hamster buccal pouch (HBP) carcinogenesis model based on its ability to modulate NF-kappa B and Wnt signaling pathways and induce apoptosis.Methods: We determined the effect of dietary supplementation of astaxanthin on the oncogenic signaling pathways - NF-kappa B and Wnt/beta-catenin, their upstream activator kinases - Erk/MAPK and PI-3K/Akt, and the downstream event - apoptosis evasion by real-time quantitative RT-PCR, western blot, and immunohistochemical analyses.Results: We found that astaxanthin inhibits NF-kappa B and Wnt signaling by downregulating the key regulatory enzymes IKK beta and GSK-3 beta. Analysis of gene expression and docking interactions revealed that inhibition of these pathways may be mediated via inactivation of the upstream signaling kinases Erk/Akt by astaxanthin. Astaxanthin also induced caspase-mediated mitochondrial apoptosis by downregulating the expression of antiapoptotic Bcl-2, p-Bad, and survivin and upregulating proapoptotic Bax and Bad, accompanied by efflux of Smac/Diablo and cytochrome-c into the cytosol, and induced cleavage of poly (ADP-ribose) polymerase (PARP).Conclusions: The results provide compelling evidence that astaxanthin exerts chemopreventive effects by concurrently inhibiting phosphorylation of transcription factors and signaling kinases and inducing intrinsic apoptosis.General significance: Astaxanthin targets key molecules in oncogenic signaling pathways and induces apoptosis and is a promising candidate agent for cancer prevention and therapy. (c) 2013 Elsevier B.V. All rights reserved.