HO-3867, a synthetic compound, inhibits the migration and invasion of ovarian carcinoma cells through downregulation of fatty acid synthase and focal adhesion kinase.
HO-3867, a synthetic compound, inhibits the migration and invasion of ovarian carcinoma cells through downregulation of fatty acid synthase and focal adhesion kinase.
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DOI：
10.1158/1541-7786.mcr-10-0201
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发表时间：
2010-09
期刊：
影响因子：
--
通讯作者：
Kuppusamy P
中科院分区：
文献类型：
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作者：
Selvendiran K;Ahmed S;Dayton A;Ravi Y;Kuppusamy ML;Bratasz A;Rivera BK;Kálai T;Hideg K;Kuppusamy P
脂肪酸合成酶（Fatty acid synthase， FAS）和局灶黏附激酶（focal adhesion kinase， FAK）在多种人类上皮肿瘤中过表达，在癌细胞的迁移和侵袭中起关键作用。因此，针对抑制FAS/FAK蛋白的策略可能具有治疗癌症的潜力。本研究的目的是确定HO-3867（一种合成化合物）对卵巢癌细胞迁移能力的影响，并了解包括FAS、FAK和相关信号蛋白参与在内的机制途径。本研究使用两种已建立的人卵巢癌细胞系A2780和SKOV3进行。10-μM HO-3867孵育24小时，可显著抑制vegf介导的细胞迁移和侵袭。HO-3867明显下调异肽酶USP2a，通过加速泛素依赖性降解，显著降低FAS和FAK蛋白水平。暴露于HO-3867细胞也显著抑制FAS活性、mRNA水平和一些下游蛋白，包括pERK1/2、pHER1、SREBP1、VEGF和MMP-2。HO-3867处理小鼠A2780异种移植瘤的Western-blot和免疫组织化学分析显示，与未处理的对照组相比，FAS、FAK、VEGF和下游蛋白水平显著降低。综上所述，HO-3867通过抑制FAS和FAK蛋白的表达/活性来抑制卵巢癌细胞的迁移和侵袭。本研究提示HO-3867分子靶向FAS和FAK可能是卵巢癌治疗的一种潜在策略。
Fatty acid synthase (FAS) and focal adhesion kinase (FAK), which are overexpressed in a variety of human epithelial tumors, play a key role in the migration and invasion of cancer cells. Hence, strategies targeted at inhibiting the FAS/FAK proteins may have therapeutic potential for cancer treatment. The goal of the present study was to determine the effect of HO-3867, a synthetic compound, on the migratory ability of ovarian cancer cells and to understand the mechanistic pathways including the involvement of FAS, FAK, and associated signaling proteins. The study was performed using two established human ovarian cancer cell lines, namely, A2780 and SKOV3. Incubation with 10-μM HO-3867 for 24 hours significantly inhibited the native as well as VEGF-mediated migration and invasion of the cells. HO-3867 significantly attenuated FAS and FAK protein levels apparently through accelerated ubiquitin-dependent degradation as shown by a clear down-regulation of isopeptidase USP2a. Exposure of cells to HO-3867 also significantly inhibited the FAS activity, mRNA levels, and a number of downstream proteins including pERK1/2, pHER1, SREBP1, VEGF, and MMP-2. Western-blot and immunohistochemical analyses of A2780 xenograft tumors in mice treated with HO-3867 showed significant reduction in FAS, FAK, VEGF, and downstream protein levels when compared to untreated control. Collectively, the results demonstrated that HO-3867 suppressed the migration and invasion of the ovarian cancer cells by inhibiting the expression/activity of FAS and FAK proteins. The study suggested that molecular targeting of FAS and FAK by HO-3867 might be a potential strategy for ovarian cancer therapy.