PDF(Pubmed)
Abstract：
The metastasis-associated protein 1/protein kinase B (MTA1/AKT) signaling pathway has been shown to cooperate in promoting prostate tumor growth. Targeted interception strategies by plant-based polyphenols, specifically stilbenes, have shown great promise against MTA1-mediated prostate cancer progression. In this study, we employed a prostate-specific transgenic mouse model with MTA1 overexpression on the background of phosphatase and tensin homolog (Pten) null (R26MTA1; Ptenf/f) and PC3M prostate cancer cells which recapitulate altered molecular pathways in advanced prostate cancer. Mechanistically, the MTA1 knockdown or pharmacological inhibition of MTA1 by gnetin C (dimer resveratrol) in cultured PC3M cells resulted in the marked inactivation of mammalian target of rapamycin (mTOR) signaling. In vivo, mice tolerated a daily intraperitoneal treatment of gnetin C (7 mg/kg bw) for 12 weeks without any sign of toxicity. Treatment with gnetin C markedly reduced cell proliferation and angiogenesis and promoted apoptosis in mice with advanced prostate cancer. Further, in addition to decreasing MTA1 levels in prostate epithelial cells, gnetin C significantly reduced mTOR signaling activity in prostate tissues, including the activity of mTOR-target proteins: p70 ribosomal protein S6 kinase (S6K) and eukaryotic translational initiation factor 4E (elF4E)-binding protein 1 (4EBP1). Collectively, these findings established gnetin C as a new natural compound with anticancer properties against MTA1/AKT/mTOR-activated prostate cancer, with potential as monotherapy and as a possible adjunct to clinically approved mTOR pathway inhibitors in the future.
摘要：
转移相关蛋白1/蛋白激酶B（MTA1/AKT）信号通路已被证明在促进前列腺肿瘤生长方面具有协同作用。植物多酚的针对性拦截策略，特别是二苯乙烯，对MTA1介导的前列腺癌进展显示出巨大的希望。在这项研究中,我们在磷酸酶和张力蛋白同源物(Pten)缺失(R26MTA1;Ptenf/f)和PC3M前列腺癌细胞的背景下,采用了MTA1过表达的前列腺特异性转基因小鼠模型,该模型概括了晚期前列腺癌的分子通路改变.机械上,在培养的PC3M细胞中，gnetinC（二聚体白藜芦醇）对MTA1的敲除或药理学抑制导致哺乳动物雷帕霉素靶蛋白（mTOR）信号显着失活。在体内,小鼠耐受每天腹膜内治疗gnetinC（7mg/kgbw）12周，没有任何毒性迹象。在患有晚期前列腺癌的小鼠中,用gnetinC处理显著降低细胞增殖和血管生成并促进细胞凋亡。Further,除了降低前列腺上皮细胞中的MTA1水平，gnetinC显着降低前列腺组织中的mTOR信号活性，包括mTOR靶蛋白的活性：p70核糖体蛋白S6激酶（S6K）和真核翻译起始因子4E（elF4E）结合蛋白1（4EBP1）。总的来说，这些发现确立了gnetinC作为一种新的天然化合物，对MTA1/AKT/mTOR激活的前列腺癌具有抗癌特性，具有作为单一疗法的潜力，并可能作为未来临床批准的mTOR途径抑制剂的辅助药物。
