Myricetin induces apoptosis by inhibiting P21 activated kinase 1 (PAK1) signaling cascade in hepatocellular carcinoma
Myricetin induces apoptosis by inhibiting P21 activated kinase 1 (PAK1) signaling cascade in hepatocellular carcinoma
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DOI：
10.1007/s11010-015-2471-6
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发表时间：
2015-09-01
影响因子：
4.3
通讯作者：
Halagowder, Devaraj
中科院分区：
文献类型：
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作者：
Iyer, Soumya C.;Gopal, Ashidha;Halagowder, Devaraj
肝细胞癌是世界范围内最常见的恶性肿瘤之一，有证据表明RAS信号通过调节ERK和PI3K等效应通路来调节肿瘤的各种标志。本研究的目的是首次了解黄酮类杨梅素对肝细胞癌中RAS信号通路下游靶分子p21激活的蛋白1(PAK1)的抑制作用。基因表达分析表明，杨梅素通过抑制ERK/Akt下游的Wnt信号通路，抑制RAS介导的信号转导，从而通过下调抗凋亡基因Bcl2和Survivin的表达，上调促凋亡基因Bax的表达，诱导内源性caspase介导的线粒体凋亡。这些结果也为杨梅素通过协同阻断MAPK/ERK和PI3K/AKT及其下游信号通路Wnt/β-catenin抑制PAK1而抑制肝癌的发生发展提供了有力的证据，因而有望成为肿瘤防治的候选药物。
Hepatocellular carcinoma is one of the most common malignancies worldwide and evidence suggests that Ras signaling regulates various hallmarks of cancer via regulating several effector pathways such as ERK and PI3K. The aim of the present study is to understand the efficacy of a flavonoid myricetin for the first time in inhibiting the downstream target p21 activated kinase 1 (PAK1) of Ras signaling pathway in hepatocellular carcinoma. The analysis of gene expression revealed that myricetin inhibits PAK1 by abrogating the Ras-mediated signaling by decelerating Wnt signaling, the downstream of Erk/Akt, thereby inducing intrinsic caspase-mediated mitochondrial apoptosis by downregulating the expression of anti-apoptotic Bcl-2 and survivin and upregulating pro-apoptotic Bax. The results also provide striking evidence that the myricetin inhibits the development of HCC by inhibiting PAK1 via coordinate abrogation of MAPK/ERK and PI3K/AKT and their downstream signaling Wnt/beta-catenin pathway, thus being a promising candidate for cancer prevention and therapy.