Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • For Subscribers
    • For Advertisers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in

Search

  • Advanced search
Molecular Pharmacology
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
Molecular Pharmacology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • For Subscribers
    • For Advertisers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Visit molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Research ArticleArticle

The Nuclear Factor κB Family Member RelB Facilitates Apoptosis of Renal Epithelial Cells Caused by Cisplatin/Tumor Necrosis Factor α Synergy by Suppressing an Epithelial to Mesenchymal Transition–Like Phenotypic Switch

Giulia Benedetti, Michiel Fokkelman, Kuan Yan, Lisa Fredriksson, Bram Herpers, John Meerman, Bob van de Water and Marjo de Graauw
Molecular Pharmacology July 2013, 84 (1) 128-138; DOI: https://doi.org/10.1124/mol.112.084053
Giulia Benedetti
Division of Toxicology, Leiden Academic Centre for Drug Research (G.B., M.F., L.F., B.H., J.M., B.v.d.W., M.d.G.), and Imaging and Bioinformatics, Leiden Institute of Advanced Computer Science (K.Y.), Leiden University, Leiden, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michiel Fokkelman
Division of Toxicology, Leiden Academic Centre for Drug Research (G.B., M.F., L.F., B.H., J.M., B.v.d.W., M.d.G.), and Imaging and Bioinformatics, Leiden Institute of Advanced Computer Science (K.Y.), Leiden University, Leiden, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kuan Yan
Division of Toxicology, Leiden Academic Centre for Drug Research (G.B., M.F., L.F., B.H., J.M., B.v.d.W., M.d.G.), and Imaging and Bioinformatics, Leiden Institute of Advanced Computer Science (K.Y.), Leiden University, Leiden, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Lisa Fredriksson
Division of Toxicology, Leiden Academic Centre for Drug Research (G.B., M.F., L.F., B.H., J.M., B.v.d.W., M.d.G.), and Imaging and Bioinformatics, Leiden Institute of Advanced Computer Science (K.Y.), Leiden University, Leiden, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bram Herpers
Division of Toxicology, Leiden Academic Centre for Drug Research (G.B., M.F., L.F., B.H., J.M., B.v.d.W., M.d.G.), and Imaging and Bioinformatics, Leiden Institute of Advanced Computer Science (K.Y.), Leiden University, Leiden, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John Meerman
Division of Toxicology, Leiden Academic Centre for Drug Research (G.B., M.F., L.F., B.H., J.M., B.v.d.W., M.d.G.), and Imaging and Bioinformatics, Leiden Institute of Advanced Computer Science (K.Y.), Leiden University, Leiden, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bob van de Water
Division of Toxicology, Leiden Academic Centre for Drug Research (G.B., M.F., L.F., B.H., J.M., B.v.d.W., M.d.G.), and Imaging and Bioinformatics, Leiden Institute of Advanced Computer Science (K.Y.), Leiden University, Leiden, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marjo de Graauw
Division of Toxicology, Leiden Academic Centre for Drug Research (G.B., M.F., L.F., B.H., J.M., B.v.d.W., M.d.G.), and Imaging and Bioinformatics, Leiden Institute of Advanced Computer Science (K.Y.), Leiden University, Leiden, The Netherlands
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF
Loading

Abstract

Cis-diamminedichloroplatinum(II) (cisplatin)–induced renal proximal tubular apoptosis is known to be preceded by actin cytoskeleton reorganization, in conjunction with disruption of cell-matrix and cell-cell adhesion. In the present study, we show that the proinflammatory cytokine tumor necrosis factor α (TNF-α) aggravated these cisplatin-induced F-actin and cell adhesion changes, which was associated with enhanced cisplatin-induced apoptosis of immortalized proximal tubular epithelial cells. TNF-α–induced RelB expression and lentiviral small hairpin RNA (shRNA)-mediated knockdown of RelB, but not other nuclear factor κB members, abrogated the synergistic apoptosis observed with cisplatin/TNF-α treatment to the level of cisplatin-induced apoptosis. This protective effect was associated with increased stress fiber formation, cell-matrix, and cell-cell adhesion in the shRNARelB (shRelB) cells during cisplatin/TNF-α treatment, mimicking an epithelial-to-mesenchymal phenotypic switch. Indeed, gene array analysis revealed that knockdown of RelB was associated with upregulation of several actin regulatory genes, including Snai2 and the Rho GTPase proteins Rhophilin and Rho guanine nucleotide exchange factor 3 (ARHGEF3). Pharmacological inhibition of Rho kinase signaling re-established the synergistic apoptosis induced by combined cisplatin/TNF-α treatment of shRelB cells. In conclusion, our study shows for the first time that RelB is required for the cisplatin/TNF-α–induced cytoskeletal reorganization and apoptosis in renal cells by controlling a Rho kinase–dependent signaling network.

Footnotes

    • Received November 26, 2012.
    • Accepted April 26, 2013.
  • This work was performed as part of the Netherlands Toxicogenomics Center/Netherlands Genomics Initiative supported by the Dutch Organization for Scientific Research [Grant 050-06-510]; and the Dutch Top Institute Pharma project [Grant D3-201].

  • dx.doi.org/10.1124/mol.112.084053.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text

Log in using your username and password

Forgot your user name or password?

Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$35.00

Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.

PreviousNext
Back to top

In this issue

Molecular Pharmacology: 84 (1)
Molecular Pharmacology
Vol. 84, Issue 1
1 Jul 2013
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Pharmacology article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
The Nuclear Factor κB Family Member RelB Facilitates Apoptosis of Renal Epithelial Cells Caused by Cisplatin/Tumor Necrosis Factor α Synergy by Suppressing an Epithelial to Mesenchymal Transition–Like Phenotypic Switch
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
Citation Tools
Research ArticleArticle

RelB in Cisplatin/TNF-α–Induced Synergistic Apoptosis

Giulia Benedetti, Michiel Fokkelman, Kuan Yan, Lisa Fredriksson, Bram Herpers, John Meerman, Bob van de Water and Marjo de Graauw
Molecular Pharmacology July 1, 2013, 84 (1) 128-138; DOI: https://doi.org/10.1124/mol.112.084053

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Research ArticleArticle

RelB in Cisplatin/TNF-α–Induced Synergistic Apoptosis

Giulia Benedetti, Michiel Fokkelman, Kuan Yan, Lisa Fredriksson, Bram Herpers, John Meerman, Bob van de Water and Marjo de Graauw
Molecular Pharmacology July 1, 2013, 84 (1) 128-138; DOI: https://doi.org/10.1124/mol.112.084053
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • BODIPY-cyclopamine Binding to Nluc-SMO
  • Operational Models for Receptors with Multiple Agonist Sites
  • Characterization and optimization of the novel TRPM2 antagonist tatM2NX
Show more Articles

Similar Articles

  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Molecular Pharmacology
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0111 (Online)

Copyright © 2019 by the American Society for Pharmacology and Experimental Therapeutics