title: Vimentin is a novel anti-cancer therapeutic target; insights from in vitro and in vivo mice xenograft studies.
abstract: 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.
authors.affiliation: Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Guy
authors.initials: G
authors.lastname: Lahat
authors.forename: Quan-Sheng
authors.initials: QS
authors.lastname: Zhu
authors.forename: Kai-Lieh
authors.initials: KL
authors.lastname: Huang
authors.forename: Suizhao
authors.initials: S
authors.lastname: Wang
authors.forename: Svetlana
authors.initials: S
authors.lastname: Bolshakov
authors.forename: Jeffery
authors.initials: J
authors.lastname: Liu
authors.forename: Keila
authors.initials: K
authors.lastname: Torres
authors.forename: Robert R
authors.initials: RR
authors.lastname: Langley
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.forename: Mien Chie
authors.initials: MC
authors.lastname: Hung
authors.forename: Dina
authors.initials: D
authors.lastname: Lev
mesh_terms: 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
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D014746:Vimentin; D054358:Withanolides; C009684:withaferin A