Vimentin is a novel anti-cancer therapeutic target; insights from in vitro and in vivo mice xenograft studies.
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.


RESULTS
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.


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.
Lahat
Guy
G
Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
Zhu
Quan-Sheng
QS
Huang
Kai-Lieh
KL
Wang
Suizhao
S
Bolshakov
Svetlana
S
Liu
Jeffery
J
Torres
Keila
K
Langley
Robert R
RR
Lazar
Alexander J
AJ
Hung
Mien Chie
MC
Lev
Dina
D
D020533:Angiogenesis Inhibitors; D000818:Animals; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D059630:Mesenchymal Stem Cells; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology; D014746:Vimentin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054358:Withanolides / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D014746:Vimentin; D054358:Withanolides; C009684:withaferin A