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

144 Citations (Scopus)

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)
Article numbere10105
JournalPLoS One
Volume5
Issue number4
DOIs
StatePublished - 2010
Externally publishedYes

Fingerprint

vimentin
Vimentin
Heterografts
therapeutics
neoplasms
mice
Neoplasms
sarcoma
Sarcoma
caspases
Therapeutics
Tissue
Epithelial-Mesenchymal Transition
Caspases
Tumors
In Vitro Techniques
apoptosis
cells
Apoptosis
Cell signaling

ASJC Scopus subject areas

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

Cite this

Vimentin is a novel anti-cancer therapeutic target; insights from In Vitro and In Vivo mice xenograft studies. / Lahat, Guy; Zhu, Quan Sheng; Huang, Kai-Lieh; Wang, Suizhao; Bolshakov, Svetlana; Liu, Jeffery; Torres, Keila; Langley, Robert R.; Lazar, Alexander J.; Hung, Mien Chie; Lev, Dina.

In: PLoS One, Vol. 5, No. 4, e10105, 2010.

Research output: Contribution to journalArticle

Lahat, G, Zhu, QS, Huang, K-L, Wang, S, Bolshakov, S, Liu, J, Torres, K, Langley, RR, Lazar, AJ, Hung, MC & Lev, D 2010, 'Vimentin is a novel anti-cancer therapeutic target; insights from In Vitro and In Vivo mice xenograft studies', PLoS One, vol. 5, no. 4, e10105. https://doi.org/10.1371/journal.pone.0010105
Lahat, Guy ; Zhu, Quan Sheng ; Huang, Kai-Lieh ; Wang, Suizhao ; Bolshakov, Svetlana ; Liu, Jeffery ; Torres, Keila ; Langley, Robert R. ; Lazar, Alexander J. ; Hung, Mien Chie ; Lev, Dina. / Vimentin is a novel anti-cancer therapeutic target; insights from In Vitro and In Vivo mice xenograft studies. In: PLoS One. 2010 ; Vol. 5, No. 4.
@article{ab29a2acfb084184b466d9021692c48f,
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. 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.",
author = "Guy Lahat and Zhu, {Quan Sheng} and Kai-Lieh Huang and Suizhao Wang and Svetlana Bolshakov and Jeffery Liu and Keila Torres and Langley, {Robert R.} and Lazar, {Alexander J.} and Hung, {Mien Chie} and Dina Lev",
year = "2010",
doi = "10.1371/journal.pone.0010105",
language = "English (US)",
volume = "5",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "4",

}

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.

UR - http://www.scopus.com/inward/record.url?scp=77956301589&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77956301589&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0010105

DO - 10.1371/journal.pone.0010105

M3 - Article

VL - 5

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 4

M1 - e10105

ER -