Vimentin is a novel anti-cancer therapeutic target; insights from in vitro and in vivo mice xenograft studies.
Vimentin is a novel anti-cancer therapeutic target; insights from in vitro and in vivo mice xenograft studies.
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DOI：
10.1371/journal.pone.0010105
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发表时间：
2010-04-16
期刊：
影响因子：
3.7
通讯作者：
Lev D
中科院分区：
文献类型：
--
作者：
Lahat G;Zhu QS;Huang KL;Wang S;Bolshakov S;Liu J;Torres K;Langley RR;Lazar AJ;Hung MC;Lev D
波形蛋白是一种普遍存在的间充质中间丝，支持静止细胞的机械结构完整性，同时通过活化细胞中的动态组装/拆卸参与粘附、迁移、存活和细胞信号传导过程。软组织肉瘤和一些表现出“上皮向间质转化”表型的上皮癌表达波形蛋白。Withaferin-A是一种天然衍生的生物活性化合物，可以分子靶向波形蛋白，因此我们试图评估其在体外和体内对肿瘤生长的影响，从而阐明波形蛋白在药物诱导的反应中的作用。Withaferin-A在表达波形蛋白的肿瘤细胞中引起明显的凋亡和波形蛋白裂解，但在正常间充质细胞中明显较少。波形蛋白敲低后，或通过半胱天冬酶抑制剂阻断半胱天冬酶诱导的波形蛋白降解或过度表达突变的半胱天冬酶抗性波形蛋白，这种促凋亡反应被废除。证明了Withaferin-A的显著抗血管生成作用，在非增殖内皮细胞中仅观察到最小的作用。此外，在一组软组织肉瘤异种移植实验中，Withaferin-A显著阻断软组织肉瘤生长、局部复发和转移。凋亡、血管生成减少和波形蛋白降解均见于Withaferin-A处理的标本中。鉴于这些发现，评估Withaferin-A，其类似物，或其他抗波形蛋白治疗方法在软组织肉瘤和“上皮间质转化”的临床背景是必要的。
Vimentin is a ubiquitous mesenchymal intermediate filament supporting mechano-structural integrity of quiescent cells while participating in adhesion, migration, survival, and cell signaling processes via dynamic assembly/disassembly in activated cells. Soft tissue sarcomas and some epithelial cancers exhibiting “epithelial to mesenchymal transition” phenotypes express vimentin. Withaferin-A, a naturally derived bioactive compound, may molecularly target vimentin, so we sought to evaluate its effects on tumor growth in vitro and in vivo thereby elucidating the role of vimentin in drug-induced responses. Withaferin-A elicited marked apoptosis and vimentin cleavage in vimentin-expressing tumor cells but significantly less in normal mesenchymal cells. This proapoptotic response was abrogated after vimentin knockdown or by blockade of caspase-induced vimentin degradation via caspase inhibitors or overexpression of mutated caspase-resistant vimentin. Pronounced anti-angiogenic effects of Withaferin-A were demonstrated, with only minimal effects seen in non-proliferating endothelial cells. Moreover, Withaferin-A significantly blocked soft tissue sarcoma growth, local recurrence, and metastasis in a panel of soft tissue sarcoma xenograft experiments. Apoptosis, decreased angiogenesis, and vimentin degradation were all seen in Withaferin-A treated specimens. In light of these findings, evaluation of Withaferin-A, its analogs, or other anti-vimentin therapeutic approaches in soft tissue sarcoma and “epithelial to mesenchymal transition” clinical contexts is warranted.
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DOI：
10.1073/pnas.83.9.2894
发表时间：
1986-05-01
影响因子：
11.1
作者：
BENZEEV, A;AMSTERDAM, A
通讯作者：
AMSTERDAM, A
影响因子：
5.4
作者：
Barberis, Laura;Pasquali, Christian;Hirsch, Emilio
通讯作者：
Hirsch, Emilio
影响因子：
5.4
作者：
ALHINDAWI, MK;ALKHAFAJI, SH;ABDULNABI, MH
通讯作者：
ABDULNABI, MH
影响因子：
45.3
作者：
de Alava, E;Kawai, A;Ladanyi, M
通讯作者：
Ladanyi, M
影响因子：
12.4
作者：
Byun, Y;Chen, F;Cryns, VL
通讯作者：
Cryns, VL