Dysregulated fibronectin trafficking by Hsp90 inhibition restricts prostate cancer cell invasion.
Dysregulated fibronectin trafficking by Hsp90 inhibition restricts prostate cancer cell invasion.
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DOI：
10.1038/s41598-018-19871-4
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发表时间：
2018-02-01
影响因子：
4.6
通讯作者：
Butler LM
中科院分区：
文献类型：
--
作者：
Armstrong HK;Gillis JL;Johnson IRD;Nassar ZD;Moldovan M;Levrier C;Sadowski MC;Chin MY;Tomlinson Guns ES;Tarulli G;Lynn DJ;Brooks DA;Selth LA;Centenera MM;Butler LM
分子伴侣Hsp 90在前列腺癌（PCa）中过表达，并负责多种癌蛋白的折叠、稳定和成熟，这些癌蛋白与PCa进展有关。与临床上无效的第一类Hsp 90抑制剂如17-烯丙基氨基-去甲氧基格尔德霉素（17-AAG）相比，第二代抑制剂AUY 922具有更大的溶解度和功效。在此，患者来源的PCa外植体的转录组学和蛋白质组学分析鉴定了细胞骨架组织在AUY 922处理下高度富集。在PCa细胞系中的验证显示，与媒介物或17-AAG相比，AUY 922引起细胞形态的显著改变，并抑制细胞运动性和侵袭，伴随着关键细胞外基质蛋白如纤连蛋白（FN 1）的失调。有趣的是，虽然AUY 922增加了FN 1的表达，但FN 1分泌显著减少。这导致FN 1蛋白在晚期内体内的胞质积累，表明AUY 922破坏囊泡分泌运输途径。通过siRNA敲低来消耗FN 1显著降低PCa细胞的侵袭能力，表型模仿AUY 922。这些结果突出了AUY 922的新作用机制，超出了其对细胞有丝分裂和存活的既定作用，此外，还鉴定了细胞外基质货物递送作为治疗侵袭性PCa的潜在治疗靶点。
The molecular chaperone Hsp90 is overexpressed in prostate cancer (PCa) and is responsible for the folding, stabilization and maturation of multiple oncoproteins, which are implicated in PCa progression. Compared to first-in-class Hsp90 inhibitors such as 17-allylamino-demethoxygeldanamycin (17-AAG) that were clinically ineffective, second generation inhibitor AUY922 has greater solubility and efficacy. Here, transcriptomic and proteomic analyses of patient-derived PCa explants identified cytoskeletal organization as highly enriched with AUY922 treatment. Validation in PCa cell lines revealed that AUY922 caused marked alterations to cell morphology, and suppressed cell motility and invasion compared to vehicle or 17-AAG, concomitant with dysregulation of key extracellular matrix proteins such as fibronectin (FN1). Interestingly, while the expression of FN1 was increased by AUY922, FN1 secretion was significantly decreased. This resulted in cytosolic accumulation of FN1 protein within late endosomes, suggesting that AUY922 disrupts vesicular secretory trafficking pathways. Depletion of FN1 by siRNA knockdown markedly reduced the invasive capacity of PCa cells, phenocopying AUY922. These results highlight a novel mechanism of action for AUY922 beyond its established effects on cellular mitosis and survival and, furthermore, identifies extracellular matrix cargo delivery as a potential therapeutic target for the treatment of aggressive PCa.
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外泌体赋予促生存信号，以改变周围环境中前列腺细胞的表型。
影响因子：
--
作者：
Hosseini-Beheshti E;Choi W;Weiswald LB;Kharmate G;Ghaffari M;Roshan-Moniri M;Hassona MD;Chan L;Chin MY;Tai IT;Rennie PS;Fazli L;Tomlinson Guns ES
通讯作者：
Tomlinson Guns ES
NVP-AUY922：一种小分子 HSP90 抑制剂，在临床前乳腺癌模型中具有有效的抗肿瘤活性。
DOI：
10.1186/bcr1996
发表时间：
2008
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Jensen MR;Schoepfer J;Radimerski T;Massey A;Guy CT;Brueggen J;Quadt C;Buckler A;Cozens R;Drysdale MJ;Garcia-Echeverria C;Chène P
通讯作者：
Chène P
影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
4.3
作者：
Cox TR;Erler JT
通讯作者：
Erler JT
影响因子：
2.7
作者：
Beswick, RW;Ambrose, HE;Wagner, SD
通讯作者：
Wagner, SD