Honokiol abrogates leptin-induced tumor progression by inhibiting Wnt1-MTA1-β-catenin signaling axis in a microRNA-34a dependent manner.
Honokiol abrogates leptin-induced tumor progression by inhibiting Wnt1-MTA1-β-catenin signaling axis in a microRNA-34a dependent manner.
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DOI：
10.18632/oncotarget.3844
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发表时间：
2015-06-30
期刊：
影响因子：
--
通讯作者：
Sharma D
中科院分区：
文献类型：
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作者：
Avtanski DB;Nagalingam A;Kuppusamy P;Bonner MY;Arbiser JL;Saxena NK;Sharma D
肥胖严重影响乳腺癌的风险、进展和预后。由于肥胖的分子效应在很大程度上是由脂肪细胞因子瘦素介导的，因此，寻找有效的新策略来拮抗瘦素的肿瘤效应对于破坏肥胖-癌症轴是期望的。本研究旨在检测广玉兰多酚类化合物和厚朴酚（HNK）对瘦素致癌作用的影响，并系统阐明其作用机制。我们的研究结果表明，HNK显着抑制瘦素诱导的乳腺癌细胞的生长，侵袭，迁移和瘦素诱导的乳腺肿瘤异种移植物的生长。使用磷酸激酶筛选阵列，我们发现HNK抑制瘦素信号网络的关键分子的磷酸化和激活。具体地，HNK在体外和体内抑制瘦素诱导的Wnt 1-MTA 1-β-连环蛋白信号传导。最后，发现miR-34 a在HNK介导的Wnt 1-MTA 1-β-catenin轴抑制中的不可或缺的作用。HNK抑制Stat 3磷酸化，消除其对miR-34 a启动子的募集，并且这种阻遏物-Stat 3的释放导致miR-34 a活化，从而导致Wnt 1-MTA 1-β-连环蛋白抑制。因此，HNK治疗以与miR-34 a的活化和MTA 1-β-连环蛋白的抑制相关的方式抑制饮食诱导的肥胖小鼠模型（表现出高瘦素水平）中的乳腺肿瘤生长。这些数据首次提供了HNK的瘦素拮抗剂潜力的体外和体内证据，揭示了HNK与miR 34 a和Wnt 1-MTA 1-β-连环蛋白轴之间的串扰。
Obesity greatly influences risk, progression and prognosis of breast cancer. As molecular effects of obesity are largely mediated by adipocytokine leptin, finding effective novel strategies to antagonize neoplastic effects of leptin is desirable to disrupt obesity-cancer axis. Present study is designed to test the efficacy of honokiol (HNK), a bioactive polyphenol from Magnolia grandiflora, against oncogenic actions of leptin and systematically elucidate the underlying mechanisms. Our results show that HNK significantly inhibits leptin-induced breast-cancer cell-growth, invasion, migration and leptin-induced breast-tumor-xenograft growth. Using a phospho-kinase screening array, we discover that HNK inhibits phosphorylation and activation of key molecules of leptin-signaling-network. Specifically, HNK inhibits leptin-induced Wnt1-MTA1-β-catenin signaling in vitro and in vivo. Finally, an integral role of miR-34a in HNK-mediated inhibition of Wnt1-MTA1-β-catenin axis was discovered. HNK inhibits Stat3 phosphorylation, abrogates its recruitment to miR-34a promoter and this release of repressor-Stat3 results in miR-34a activation leading to Wnt1-MTA1-β-catenin inhibition. Accordingly, HNK treatment inhibited breast tumor growth in diet-induced-obese mouse model (exhibiting high leptin levels) in a manner associated with activation of miR-34a and inhibition of MTA1-β-catenin. These data provide first in vitro and in vivo evidence for the leptin-antagonist potential of HNK revealing a crosstalk between HNK and miR34a and Wnt1-MTA1-β-catenin axis.