Chemopreventive activity of plant flavonoid isorhamnetin in colorectal cancer is mediated by oncogenic Src and β-catenin.
Chemopreventive activity of plant flavonoid isorhamnetin in colorectal cancer is mediated by oncogenic Src and β-catenin.
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DOI：
10.1158/0008-5472.can-13-0525
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发表时间：
2013-09-01
期刊：
影响因子：
11.2
通讯作者：
Bobe G
中科院分区：
文献类型：
--
作者：
Saud SM;Young MR;Jones-Hall YL;Ileva L;Evbuomwan MO;Wise J;Colburn NH;Kim YS;Bobe G
对息肉预防试验的分析显示，富含异鼠李素的饮食与晚期腺瘤复发风险降低之间存在关联;然而，异鼠李素的化学保护作用的机制仍不清楚。在这里，我们证明，异鼠李素防止结肠直肠肿瘤的FVB/N小鼠治疗的化学致癌物氧化偶氮甲烷（AOM），随后暴露于结肠刺激性葡聚糖硫酸钠（DSS）。饮食异鼠李素降低死亡率，肿瘤数量和肿瘤负荷分别为62%，35%和59%。磁共振成像，组织病理学和免疫组化分析表明，饮食异鼠李素解决DSS诱导的炎症反应比对照饮食更快。异鼠李素可抑制AOM/DSS诱导的c-Src激活和β-catenin核转位，同时促进Src家族酪氨酸激酶C末端Src激酶（CSK）的表达。类似地，在HT-29结肠癌细胞中，异鼠李素通过诱导CSK的表达来抑制致癌Src活性和β-连环蛋白核转位，如通过RNAi敲低CSK所证实的。我们的观察结果表明，异鼠李素在结肠癌中的化学保护作用与其抗炎活性及其对致癌Src活性的抑制和随后的核β-连环蛋白的损失有关，这些活性依赖于CSK表达。
Analysis of the Polyp Prevention Trial showed an association between isorhamnetin-rich diet and a reduced risk of advanced adenoma recurrence; however, the mechanism of isorhamnetin’s chemoprotective effects remains unclear. Here we demonstrate that isorhamnetin prevents colorectal tumorigenesis of FVB/N mice treated with the chemical carcinogen azoxymethane (AOM) and subsequently exposed to colonic irritant dextran sodium sulfate (DSS). Dietary isorhamnetin decreased mortality, tumor number, and tumor burden by 62%, 35%, and 59%, respectively. Magnetic resonance imaging, histopathology, and immunohistochemical analysis revealed that dietary isorhamnetin resolved the DSS-induced inflammatory response faster than control diet. Isorhamnetin inhibited AOM/DSS induced oncogenic c-Src activation and β-catenin nuclear translocation, while promoting the expression of C-terminal Src Kinase (CSK), a negative regulator of Src family of tyrosine kinases. Similarly, in HT-29 colon cancer cells, isorhamnetin inhibited oncogenic Src activity and β-catenin nuclear translocation by inducing expression of CSK, as verified by RNAi knock down of CSK. Our observations suggest the chemoprotective effects of isorhamnetin in colon cancer are linked to its anti-inflammatory activities and its inhibition of oncogenic Src activity and consequential loss of nuclear β-catenin, activities that are dependent on CSK expression.