Novel pharmacologic targeting of tight junctions and focal adhesions in prostate cancer cells.
Novel pharmacologic targeting of tight junctions and focal adhesions in prostate cancer cells.
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DOI：
10.1371/journal.pone.0086238
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kyprianou N
中科院分区：
文献类型：
--
作者：
Hensley PJ;Desiniotis A;Wang C;Stromberg A;Chen CS;Kyprianou N
癌细胞对由肿瘤微环境维持的异常信号驱动的anoikis的抗性赋予了高侵袭潜力和治疗抗性。我们最近开发了一种新型的喹唑啉铅Doxazosin®衍生物DZ-50，它可以通过anoikis抑制肿瘤的生长和转移。通过对人前列腺癌细胞DU-145的全基因组分析，确定了DZ-50的主要下调靶点，包括参与局灶黏着完整性（纤连蛋白、整合素-α6和talin）、紧密连接形成（claudin-11）、胰岛素生长因子结合蛋白3 （IGFBP-3）和血管生成调节剂血栓反应蛋白1 （TSP-1）的基因。共聚焦显微镜显示，在两种雄激素不依赖型人前列腺癌细胞系PC-3和DU-145中，这些基因靶点的下调导致局灶黏附和紧密连接的结构破坏，导致细胞存活、迁移和对细胞外基质（ECM）成分的黏附降低。通过过度表达talin-1和/或将细胞暴露于富含纤维连接蛋白的环境中来稳定细胞- ecm相互作用，可以减轻DZ-50的影响。细胞内局灶粘附信号效应因子talin-1和整合素连接激酶（ILK）的表达缺失使人前列腺癌对anoikis敏感。我们的研究结果表明，DZ-50的抗肿瘤作用是通过靶向关键的功能细胞间相互作用、局灶性粘连和紧密连接发挥作用的，支持了该药物治疗晚期前列腺癌的治疗意义。
Cancer cell resistance to anoikis driven by aberrant signaling sustained by the tumor microenvironment confers high invasive potential and therapeutic resistance. We recently generated a novel lead quinazoline-based Doxazosin® derivative, DZ-50, which impairs tumor growth and metastasis via anoikis. Genome-wide analysis in the human prostate cancer cell line DU-145 identified primary downregulated targets of DZ-50, including genes involved in focal adhesion integrity (fibronectin, integrin-α6 and talin), tight junction formation (claudin-11) as well as insulin growth factor binding protein 3 (IGFBP-3) and the angiogenesis modulator thrombospondin 1 (TSP-1). Confocal microscopy demonstrated structural disruption of both focal adhesions and tight junctions by the downregulation of these gene targets, resulting in decreased cell survival, migration and adhesion to extracellular matrix (ECM) components in two androgen-independent human prostate cancer cell lines, PC-3 and DU-145. Stabilization of cell-ECM interactions by overexpression of talin-1 and/or exposing cells to a fibronectin-rich environment mitigated the effect of DZ-50. Loss of expression of the intracellular focal adhesion signaling effectors talin-1 and integrin linked kinase (ILK) sensitized human prostate cancer to anoikis. Our findings suggest that DZ-50 exerts its antitumor effect by targeting the key functional intercellular interactions, focal adhesions and tight junctions, supporting the therapeutic significance of this agent for the treatment of advanced prostate cancer.
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影响因子：
3.2
作者：
Matuszak EA;Kyprianou N
通讯作者：
Kyprianou N
影响因子：
3.7
作者：
Kong D;Banerjee S;Ahmad A;Li Y;Wang Z;Sethi S;Sarkar FH
通讯作者：
Sarkar FH
影响因子：
3.7
作者：
Hensley P;Mishra M;Kyprianou N
通讯作者：
Kyprianou N
DOI：
10.1016/b978-0-12-386039-2.00004-3
发表时间：
2011
影响因子：
--
作者：
Desiniotis A;Kyprianou N
通讯作者：
Kyprianou N
影响因子：
64.5
作者：
Chan CH;Morrow JK;Li CF;Gao Y;Jin G;Moten A;Stagg LJ;Ladbury JE;Cai Z;Xu D;Logothetis CJ;Hung MC;Zhang S;Lin HK
通讯作者：
Lin HK