Inverse agonism at the Na/K-ATPase receptor reverses EMT in prostate cancer cells.
Inverse agonism at the Na/K-ATPase receptor reverses EMT in prostate cancer cells.
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DOI：
10.1002/pros.24144
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发表时间：
2021-07
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影响因子：
--
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中科院分区：
文献类型：
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钠/钾 - ATP酶α1（NKA）的表面表达在原发性前列腺肿瘤中显著降低，在骨转移病灶中进一步下降。在此，我们表明NKA细胞表面表达的缺失通过激活Src/FAK通路降低E - 钙黏蛋白的表达并增加c - Myc的表达，从而诱导上皮 - 间质转化（EMT），促进前列腺癌（PCa）的转移潜能和肿瘤生长。从机制上讲，前列腺癌中NKA表面表达降低是由于受体NKA/Src复合物的激活导致内吞作用增加。利用高通量NKA配体筛选平台，我们发现MB5是NKA/Src受体复合物的反向激动剂，能够阻断NKA的内吞作用。MB5处理增加了前列腺癌中NKA的表达和E - 钙黏蛋白，逆转了EMT，从而降低了球体模型和肿瘤异种移植物的侵袭和生长。因此，我们确定了一种迄今尚未被认识的调节前列腺癌EMT和侵袭性的机制，并首次证明了识别受体NKA/Src复合物反向激动剂及其作为抗癌药物潜在用途的可行性。因此，我们得出结论，α1 NKA的细胞表面表达可作为开发针对侵袭性前列腺癌的新疗法的靶点，并且MB5可作为针对转移性前列腺癌中EMT的药物开发的原型。
The surface expression of Na/K-ATPase α1 (NKA) is significantly reduced in primary prostate tumors and further decreased in bone metastatic lesions. Here, we show that the loss of cell surface expression of NKA induces epithelial mesenchymal transition (EMT) and promotes metastatic potential and tumor growth of prostate cancer (PCa) by decreasing the expression of E-cadherin and increasing c-Myc expression via the activation of Src/FAK pathways. Mechanistically, reduced surface expression of NKA in PCa is due to increased endocytosis through the activation of receptor NKA/Src complex. Using a high throughput NKA ligand screening platform, we have discovered MB5 as an inverse agonist of the NKA/Src receptor complex, capable of blocking the endocytosis of NKA. MB5 treatment increased NKA expression and E-cadherin in PCa, which reversed EMT and consequently decreased the invasion and growth of spheroid models and tumor xenografts. Thus, we have identified a hitherto unrecognized mechanism that regulates EMT and invasiveness of PCa, and demonstrated for the first time the feasibility of identifying inverse agonists of receptor NKA/Src complex and their potential utility as anti-cancer drugs. We, therefore, conclude that cell surface expression of α1 NKA can be targeted for the development of new therapeutics against aggressive PCa, and that MB5 may serve as a prototype for drug development against EMT in metastatic PCa.
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影响因子：
5.7
作者：
Inge, Landon J.;Rajasekaran, Sigrid A.;Rajasekaran, Ayyappan K.
通讯作者：
Rajasekaran, Ayyappan K.
影响因子：
4
作者：
Baker Bechmann M;Rotoli D;Morales M;Maeso Mdel C;García Mdel P;Ávila J;Mobasheri A;Martín-Vasallo P
通讯作者：
Martín-Vasallo P
影响因子：
3.7
作者：
Banerjee M;Duan Q;Xie Z
通讯作者：
Xie Z
DOI：
10.3390/molecules22060990
发表时间：
2017-06-14
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Cui X;Xie Z
通讯作者：
Xie Z
影响因子：
4.8
作者：
Liang, Man;Cai, Ting;Xie, Zi-Jian
通讯作者：
Xie, Zi-Jian