Reversion of epithelial-mesenchymal transition by a novel agent DZ-50 via IGF binding protein-3 in prostate cancer cells.
Reversion of epithelial-mesenchymal transition by a novel agent DZ-50 via IGF binding protein-3 in prostate cancer cells.
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DOI：
10.18632/oncotarget.19659
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发表时间：
2017-10-03
期刊：
影响因子：
--
通讯作者：
Kyprianou N
中科院分区：
文献类型：
--
作者：
Cao Z;Koochekpour S;Strup SE;Kyprianou N
转化生长因子-β1（TGF-β1）和胰岛素样生长因子（IGF）轴的失调与前列腺癌进展中的反应性基质动力学有关。IGF结合蛋白-3（IGFBP 3）的诱导是由基质重塑启动的，可能是前列腺癌的潜在治疗靶点。在先前的研究中，基于喹唑啉的铅多沙唑嗪®衍生物DZ-50通过靶向参与粘着斑、抗失巢凋亡和上皮-间质转化（EMT）的蛋白质来损害前列腺肿瘤生长。这项研究表明，DZ-50增加上皮标志物E-钙粘蛋白的表达，并减少人前列腺癌细胞中的间质标志物N-钙粘蛋白。在DU-145细胞中，DZ-50对EMT向间充质上皮转化（MET）的作用被talin 1过表达抑制，talin 1是一种促进失巢凋亡抵抗和肿瘤侵袭的粘着斑调节剂。DZ-50处理人前列腺癌细胞和癌症相关成纤维细胞（CAF）在mRNA和蛋白质水平下调IGFBP 3表达。在TGF-β1反应性LNCaPTβRII中，TGF-β1通过拮抗药物诱导的核IGFBP 3减少来逆转DZ-50诱导的MET。此外，与CAF共培养促进前列腺癌上皮细胞侵袭，这种作用被DZ-50显著抑制。我们的研究结果表明，先导化合物DZ-50通过靶向IGFBP 3并介导EMT转化为MET来抑制前列腺癌上皮细胞的侵袭性。本研究整合了DZ-50的作用机制，进一步支持了该化合物在治疗晚期转移性前列腺癌中的治疗价值。
Dysregulation of transforming growth factor-β1 (TGF-β1) and insulin-like growth factor (IGF) axis has been linked to reactive stroma dynamics in prostate cancer progression. IGF binding protein-3 (IGFBP3) induction is initiated by stroma remodeling and could represent a potential therapeutic target for prostate cancer. In previous studies a lead quinazoline-based Doxazosin® derivative, DZ-50, impaired prostate tumor growth by targeting proteins involved in focal adhesion, anoikis resistance and epithelial-mesenchymal-transition (EMT). This study demonstrates that DZ-50 increased expression of the epithelial marker E-cadherin, and decreased the mesenchymal marker N-cadherin in human prostate cancer cells. In DU-145 cells, the effect of DZ-50 on EMT towards mesenchymal epithelial transition (MET) was inhibited by talin1 overexpression, a focal adhesion regulator promoting anoikis resistance and tumor invasion. DZ-50 treatment of human prostate cancer cells and cancer-associated fibroblasts (CAFs) downregulated IGFBP3 expression at mRNA and protein level. In TGF-β1 responsive LNCaPTβRII, TGF-β1 reversed DZ-50-induced MET by antagonizing the drug-induced decrease of nuclear IGFBP3. Furthermore, co-culture with CAFs promoted prostate cancer epithelial cell invasion, an effect that was significantly inhibited by DZ-50. Our findings demonstrate that the lead compound, DZ-50, inhibited the invasive properties of prostate cancer epithelial cells by targeting IGFBP3 and mediating EMT conversion to MET. This study integrated the mechanisms underlying the effect of DZ-50 and further supported the therapeutic value of this compound in the treatment of advanced metastatic prostate cancer.
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影响因子：
2.6
作者：
Cao Z;Kyprianou N
通讯作者：
Kyprianou N
影响因子：
3.7
作者：
Hensley PJ;Desiniotis A;Wang C;Stromberg A;Chen CS;Kyprianou N
通讯作者：
Kyprianou N
DOI：
10.1158/1078-0432.ccr-13-1694
发表时间：
2013-09-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Freeman MR;Li Q;Chung LW
通讯作者：
Chung LW
影响因子：
8
作者：
Lin, M. Z.;Marzec, K. A.;Baxter, R. C.
通讯作者：
Baxter, R. C.
影响因子：
5.6
作者：
CHEN, JC;SHAO, ZM;FONTANA, JA
通讯作者：
FONTANA, JA