TY - JOUR
T1 - Vimentin is a novel anti-cancer therapeutic target; insights from In Vitro and In Vivo mice xenograft studies
AU - Lahat, Guy
AU - Zhu, Quan Sheng
AU - Huang, Kai Lieh
AU - Wang, Suizhao
AU - Bolshakov, Svetlana
AU - Liu, Jeffery
AU - Torres, Keila
AU - Langley, Robert R.
AU - Lazar, Alexander J.
AU - Hung, Mien Chie
AU - Lev, Dina
PY - 2010
Y1 - 2010
N2 - Background: 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. Methods and Findings: 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 nonproliferating 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. Conclusions: 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.
AB - Background: 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. Methods and Findings: 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 nonproliferating 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. Conclusions: 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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U2 - 10.1371/journal.pone.0010105
DO - 10.1371/journal.pone.0010105
M3 - Article
C2 - 20419128
AN - SCOPUS:77956301589
SN - 1932-6203
VL - 5
SP - 1
EP - 19
JO - PloS one
JF - PloS one
IS - 4
ER -