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.
转移相关蛋白1/蛋白激酶B（MTA1/AKT）信号通路已被证实协同促进前列腺肿瘤生长。基于植物的多酚类物质，特别是芪类化合物，通过靶向干预策略在抑制MTA1介导的前列腺癌进展方面展现出巨大潜力。本研究采用前列腺特异性转基因小鼠模型（在磷酸酶与张力蛋白同源物（Pten）缺失背景下过表达MTA1的R26MTA1;Ptenf/f小鼠）以及能重现晚期前列腺癌分子通路改变的PC3M前列腺癌细胞系。机制研究表明，在培养的PC3M细胞中敲低MTA1或通过翼核果素C（二聚白藜芦醇）进行药理学抑制，可显著抑制哺乳动物雷帕霉素靶蛋白（mTOR）信号通路活性。在体实验中，小鼠每日腹腔注射翼核果素C（7毫克/千克体重）持续12周未出现任何毒性迹象。翼核果素C治疗显著降低了晚期前列腺癌小鼠的细胞增殖和血管生成，并促进细胞凋亡。此外，除了降低前列腺上皮细胞中MTA1水平外，翼核果素C还能显著抑制前列腺组织中mTOR信号通路活性，包括其下游靶蛋白p70核糖体蛋白S6激酶（S6K）和真核翻译起始因子4E结合蛋白1（4EBP1）的活性。综上所述，这些研究结果确立了翼核果素C作为一种新型天然化合物，对MTA1/AKT/mTOR通路激活的前列腺癌具有抗癌特性，既可作为单一疗法，未来也有潜力作为临床已批准的mTOR通路抑制剂的辅助治疗手段。
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