Vimentin is a novel anti-cancer therapeutic target; insights from In Vitro and In Vivo mice xenograft studies

Guy Lahat, Quan Sheng Zhu, Kai Lieh Huang, Suizhao Wang, Svetlana Bolshakov, Jeffery Liu, Keila Torres, Robert R. Langley, Alexander J. Lazar, Mien Chie Hung, Dina Lev

Research output: Contribution to journalArticle

149 Scopus citations

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. 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.

Original languageEnglish (US)
Pages (from-to)1-19
Number of pages19
JournalPloS one
Volume5
Issue number4
DOIs
StatePublished - 2010

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Lahat, G., Zhu, Q. S., Huang, K. L., Wang, S., Bolshakov, S., Liu, J., Torres, K., Langley, R. R., Lazar, A. J., Hung, M. C., & Lev, D. (2010). Vimentin is a novel anti-cancer therapeutic target; insights from In Vitro and In Vivo mice xenograft studies. PloS one, 5(4), 1-19. https://doi.org/10.1371/journal.pone.0010105