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

Producción científica: Article › revisión exhaustiva

298 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	623-634
Número de páginas	12
Publicación	Chemistry and Biology
Volumen	14
N.º	6
DOI	https://doi.org/10.1016/j.chembiol.2007.04.010
Estado	Published - jun 25 2007

Nota bibliográfica

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.

Financiación

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.

Financiadores	Número del financiador
Fight for Sight Foundation
Kentucky Lung Cancer Research Program
NHLB
National Institutes of Health (NIH)
National Institute on Drug Abuse
National Eye Institute (NEI)	R01EY016782
National Institute of Allergy and Infectious F32-AI286447 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R01AI168214 Jason W. Rosch Diseases National Institute of Allergy and Infectious P30 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R00-AI166116 Christopher D. Radka Diseases National Institute of Allergy and Infectious T32-AI106700 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R01AI192221 Jason W. Rosch Diseases National Inst...
Burroughs Wellcome Fund
Arthritis Foundation
Kentucky Science and Engineering Foundation

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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10.1016/j.chembiol.2007.04.010

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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

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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.",

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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. ",

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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.

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JO - Chemistry and Biology

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ER -

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

Resumen

Nota bibliográfica

Financiación

ASJC Scopus subject areas

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