The Tumor Inhibitor and Antiangiogenic Agent Withaferin A Targets the Intermediate Filament Protein Vimentin

Paola Bargagna-Mohan; Adel Hamza; Yang eon Kim; Yik Khuan (Abby) Ho; Nirit Mor-Vaknin; Nicole Wendschlag; Junjun Liu; Robert M. Evans; David M. Markovitz; Chang Guo Zhan; Kyung Bo Kim; Royce Mohan

doi:10.1016/j.chembiol.2007.04.010

The Tumor Inhibitor and Antiangiogenic Agent Withaferin A Targets the Intermediate Filament Protein Vimentin

Paola Bargagna-Mohan, Adel Hamza, Yang eon Kim, Yik Khuan (Abby) Ho, Nirit Mor-Vaknin, Nicole Wendschlag, Junjun Liu, Robert M. Evans, David M. Markovitz, Chang Guo Zhan, Kyung Bo Kim, Royce Mohan

Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

277 Scopus citations

Abstract

The natural product withaferin A (WFA) exhibits antitumor and antiangiogenesis activity in vivo, which results from this drug's potent growth inhibitory activities. Here, we show that WFA binds to the intermediate filament (IF) protein, vimentin, by covalently modifying its cysteine residue, which is present in the highly conserved α-helical coiled coil 2B domain. WFA induces vimentin filaments to aggregate in vitro, an activity manifested in vivo as punctate cytoplasmic aggregates that colocalize vimentin and F-actin. WFA's potent dominant-negative effect on F-actin requires vimentin expression and induces apoptosis. Finally, we show that WFA-induced inhibition of capillary growth in a mouse model of corneal neovascularization is compromised in vimentin-deficient mice. These findings identify WFA as a chemical genetic probe of IF functions, and illuminate a potential molecular target for withanolide-based therapeutics for treating angioproliferative and malignant diseases.

Original language	English
Pages (from-to)	623-634
Number of pages	12
Journal	Chemistry and Biology
Volume	14
Issue number	6
DOIs	https://doi.org/10.1016/j.chembiol.2007.04.010
State	Published - Jun 25 2007

Bibliographical note

Funding Information:
We thank Jack Goodman from the UK Mass Spectrometry Core Facility, Greg Bauman and Jennifer Strange from Flow Cytometry Core Facility, and Mary Engle from Imaging and Histology Core Center for their expert technical assistance, and J. Ambati and A. Pearson for scientific discussions. R.M. is supported by a Fight for Sight Foundation grant-in-aid, Kentucky Science and Engineering Foundation award, and a Research to Prevent Blindness Challenge Award to the Department of Ophthalmology; C.-G.Z. by NIDA/NIH; K.B.K. by the Kentucky Lung Cancer Research Program; D.M.M is the recipient of a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, and is supported by the Arthritis Foundation and NHLB/NIH and NIAID/NIH. The authors declare no conflicts of interest.

Keywords

CELLBIO
CHEMBIOL

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

Access to Document

10.1016/j.chembiol.2007.04.010

Cite this

Bargagna-Mohan, P., Hamza, A., Kim, Y. E., Khuan (Abby) Ho, Y., Mor-Vaknin, N., Wendschlag, N., Liu, J., Evans, R. M., Markovitz, D. M., Zhan, C. G., Kim, K. B., & Mohan, R. (2007). The Tumor Inhibitor and Antiangiogenic Agent Withaferin A Targets the Intermediate Filament Protein Vimentin. Chemistry and Biology, 14(6), 623-634. https://doi.org/10.1016/j.chembiol.2007.04.010

@article{fd22a48041cb4b40bcf40845e39fba54,

title = "The Tumor Inhibitor and Antiangiogenic Agent Withaferin A Targets the Intermediate Filament Protein Vimentin",

abstract = "The natural product withaferin A (WFA) exhibits antitumor and antiangiogenesis activity in vivo, which results from this drug's potent growth inhibitory activities. Here, we show that WFA binds to the intermediate filament (IF) protein, vimentin, by covalently modifying its cysteine residue, which is present in the highly conserved α-helical coiled coil 2B domain. WFA induces vimentin filaments to aggregate in vitro, an activity manifested in vivo as punctate cytoplasmic aggregates that colocalize vimentin and F-actin. WFA's potent dominant-negative effect on F-actin requires vimentin expression and induces apoptosis. Finally, we show that WFA-induced inhibition of capillary growth in a mouse model of corneal neovascularization is compromised in vimentin-deficient mice. These findings identify WFA as a chemical genetic probe of IF functions, and illuminate a potential molecular target for withanolide-based therapeutics for treating angioproliferative and malignant diseases.",

keywords = "CELLBIO, CHEMBIOL",

author = "Paola Bargagna-Mohan and Adel Hamza and Kim, {Yang eon} and {Khuan (Abby) Ho}, Yik and Nirit Mor-Vaknin and Nicole Wendschlag and Junjun Liu and Evans, {Robert M.} and Markovitz, {David M.} and Zhan, {Chang Guo} and Kim, {Kyung Bo} and Royce Mohan",

note = "Funding Information: We thank Jack Goodman from the UK Mass Spectrometry Core Facility, Greg Bauman and Jennifer Strange from Flow Cytometry Core Facility, and Mary Engle from Imaging and Histology Core Center for their expert technical assistance, and J. Ambati and A. Pearson for scientific discussions. R.M. is supported by a Fight for Sight Foundation grant-in-aid, Kentucky Science and Engineering Foundation award, and a Research to Prevent Blindness Challenge Award to the Department of Ophthalmology; C.-G.Z. by NIDA/NIH; K.B.K. by the Kentucky Lung Cancer Research Program; D.M.M is the recipient of a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, and is supported by the Arthritis Foundation and NHLB/NIH and NIAID/NIH. The authors declare no conflicts of interest. ",

year = "2007",

month = jun,

day = "25",

doi = "10.1016/j.chembiol.2007.04.010",

language = "English",

volume = "14",

pages = "623--634",

number = "6",

}

TY - JOUR

T1 - The Tumor Inhibitor and Antiangiogenic Agent Withaferin A Targets the Intermediate Filament Protein Vimentin

AU - Bargagna-Mohan, Paola

AU - Hamza, Adel

AU - Kim, Yang eon

AU - Khuan (Abby) Ho, Yik

AU - Mor-Vaknin, Nirit

AU - Wendschlag, Nicole

AU - Liu, Junjun

AU - Evans, Robert M.

AU - Markovitz, David M.

AU - Zhan, Chang Guo

AU - Kim, Kyung Bo

AU - Mohan, Royce

N1 - Funding Information: We thank Jack Goodman from the UK Mass Spectrometry Core Facility, Greg Bauman and Jennifer Strange from Flow Cytometry Core Facility, and Mary Engle from Imaging and Histology Core Center for their expert technical assistance, and J. Ambati and A. Pearson for scientific discussions. R.M. is supported by a Fight for Sight Foundation grant-in-aid, Kentucky Science and Engineering Foundation award, and a Research to Prevent Blindness Challenge Award to the Department of Ophthalmology; C.-G.Z. by NIDA/NIH; K.B.K. by the Kentucky Lung Cancer Research Program; D.M.M is the recipient of a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, and is supported by the Arthritis Foundation and NHLB/NIH and NIAID/NIH. The authors declare no conflicts of interest.

PY - 2007/6/25

Y1 - 2007/6/25

N2 - The natural product withaferin A (WFA) exhibits antitumor and antiangiogenesis activity in vivo, which results from this drug's potent growth inhibitory activities. Here, we show that WFA binds to the intermediate filament (IF) protein, vimentin, by covalently modifying its cysteine residue, which is present in the highly conserved α-helical coiled coil 2B domain. WFA induces vimentin filaments to aggregate in vitro, an activity manifested in vivo as punctate cytoplasmic aggregates that colocalize vimentin and F-actin. WFA's potent dominant-negative effect on F-actin requires vimentin expression and induces apoptosis. Finally, we show that WFA-induced inhibition of capillary growth in a mouse model of corneal neovascularization is compromised in vimentin-deficient mice. These findings identify WFA as a chemical genetic probe of IF functions, and illuminate a potential molecular target for withanolide-based therapeutics for treating angioproliferative and malignant diseases.

AB - The natural product withaferin A (WFA) exhibits antitumor and antiangiogenesis activity in vivo, which results from this drug's potent growth inhibitory activities. Here, we show that WFA binds to the intermediate filament (IF) protein, vimentin, by covalently modifying its cysteine residue, which is present in the highly conserved α-helical coiled coil 2B domain. WFA induces vimentin filaments to aggregate in vitro, an activity manifested in vivo as punctate cytoplasmic aggregates that colocalize vimentin and F-actin. WFA's potent dominant-negative effect on F-actin requires vimentin expression and induces apoptosis. Finally, we show that WFA-induced inhibition of capillary growth in a mouse model of corneal neovascularization is compromised in vimentin-deficient mice. These findings identify WFA as a chemical genetic probe of IF functions, and illuminate a potential molecular target for withanolide-based therapeutics for treating angioproliferative and malignant diseases.

KW - CELLBIO

KW - CHEMBIOL

UR - http://www.scopus.com/inward/record.url?scp=34250346795&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34250346795&partnerID=8YFLogxK

U2 - 10.1016/j.chembiol.2007.04.010

DO - 10.1016/j.chembiol.2007.04.010

M3 - Article

C2 - 17584610

AN - SCOPUS:34250346795

SN - 1074-5521

VL - 14

SP - 623

EP - 634

JO - Chemistry and Biology

JF - Chemistry and Biology

IS - 6

ER -

The Tumor Inhibitor and Antiangiogenic Agent Withaferin A Targets the Intermediate Filament Protein Vimentin

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this