Evidence for 2-Methoxyestradiol-Mediated Inhibition of Receptor Tyrosine Kinase RON in the Management of Prostate Cancer.
Evidence for 2-Methoxyestradiol-Mediated Inhibition of Receptor Tyrosine Kinase RON in the Management of Prostate Cancer.
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DOI：
10.3390/ijms22041852
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发表时间：
2021-02-12
影响因子：
5.6
通讯作者：
Kumar AP
中科院分区：
文献类型：
--
作者：
Batth IS;Huang SB;Villarreal M;Gong J;Chakravarthy D;Keppler B;Jayamohan S;Osmulski P;Xie J;Rivas P;Bedolla R;Liss MA;Yeh IT;Reddick R;Miyamoto H;Ghosh R;Kumar AP
2-甲氧基雌二醇(2-ME2)在人体耐受性良好的多种肿瘤模型中具有抗肿瘤活性。对其作用机制的不完全了解阻碍了其作为抗肿瘤化合物的发展。我们首次确定巨噬细胞刺激蛋白1受体(MST1R)是前列腺癌细胞中2-ME2的潜在靶点。人体组织验证研究表明，与邻近的正常/良性腺体相比，前列腺癌组织中的MST1R(又名RON)蛋白水平显著升高。巨噬细胞刺激蛋白(MSP)是RON的配体，其血清水平不仅与疾病复发的风险有关，而且在非裔美国人患者的样本中也显著升高。2-ME2处理通过下调前列腺癌细胞系MST1R的mRNA表达和蛋白水平，抑制了与上皮间充质转化相关的粘附性和弹性等机械特性。2-ME2的干预显著降低了小鼠的肿瘤负担。值得注意的是，全球代谢组学研究发现，在去势动物中，循环中的胆汁酸水平显著高于2-ME2干预后的水平。综上所述，这篇论文的研究结果确定MSP是预测生化复发的潜在标记物，并提示重新定位2-ME2靶向RON信号可能是前列腺癌的一种潜在治疗方式。
2-Methoxyestradiol (2-ME2) possesses anti-tumorigenic activities in multiple tumor models with acceptable tolerability profile in humans. Incomplete understanding of the mechanism has hindered its development as an anti-tumorigenic compound. We have identified for the first-time macrophage stimulatory protein 1 receptor (MST1R) as a potential target of 2-ME2 in prostate cancer cells. Human tissue validation studies show that MST1R (a.k.a RON) protein levels are significantly elevated in prostate cancer tissues compared to adjacent normal/benign glands. Serum levels of macrophage stimulatory protein (MSP), a ligand for RON, is not only associated with the risk of disease recurrence, but also significantly elevated in samples from African American patients. 2-ME2 treatment inhibited mechanical properties such as adhesion and elasticity that are associated with epithelial mesenchymal transition by downregulating mRNA expression and protein levels of MST1R in prostate cancer cell lines. Intervention with 2-ME2 significantly reduced tumor burden in mice. Notably, global metabolomic profiling studies identified significantly higher circulating levels of bile acids in castrated animals that were decreased with 2-ME2 intervention. In summary, findings presented in this manuscript identified MSP as a potential marker for predicting biochemical recurrence and suggest repurposing 2-ME2 to target RON signaling may be a potential therapeutic modality for prostate cancer.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
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作者：
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通讯作者：
Wheeler DL
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影响因子：
15.1
作者：
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通讯作者：
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影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network