Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • 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
  • My Cart

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
  • My Cart
Molecular Pharmacology

Advanced Search

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

Cyclopentenone Prostaglandins with Dienone Structure Promote Cross-Linking of the Chemoresistance-Inducing Enzyme Glutathione Transferase P1-1

Francisco J. Sánchez-Gómez, Beatriz Díez-Dacal, María A. Pajares, Oscar Llorca and Dolores Pérez-Sala
Molecular Pharmacology October 2010, 78 (4) 723-733; DOI: https://doi.org/10.1124/mol.110.065391
Francisco J. Sánchez-Gómez
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Beatriz Díez-Dacal
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
María A. Pajares
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Oscar Llorca
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dolores Pérez-Sala
  • 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
Loading

Abstract

Glutathione transferase P1-1 (GSTP1-1) plays crucial roles in cancer chemoprevention and chemoresistance and is a key target for anticancer drug development. Oxidative stress or inhibitor-induced GSTP1-1 oligomerization leads to the activation of stress cascades and apoptosis in various tumor cells. Therefore, bivalent glutathione transferase (GST) inhibitors with the potential to interact with GST dimers are been sought as pharmacological and/or therapeutic agents. Here we have characterized GSTP1-1 oligomerization in response to various endogenous and exogenous agents. Ethacrynic acid, a classic GSTP1-1 inhibitor, 4-hydroxy-nonenal, hydrogen peroxide, and diamide all induced reversible GSTP1-1 oligomerization in Jurkat leukemia cells through the formation of disulphide bonds involving Cys47 and/or Cys101, as suggested by reducing and nonreducing SDS-polyacrylamide gel electrophoresis analysis of cysteine to serine mutants. Remarkably, the electrophilic prostanoid 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) induced irreversible GSTP1-1 oligomerization, specifically involving Cys101, a residue present in the human but not in the murine enzyme. 15d-PGJ2-induced GSTP1-1 cross-linking required the prostaglandin (PG) dienone structure and was associated with sustained c-Jun NH2-terminal kinase activation and induction of apoptosis. It is noteworthy that 15d-PGJ2 elicited GSTP1-1 cross-linking in vitro, a process that could be mimicked by other dienone cyclopentenone PG, such as Δ12-PGJ2, and by the bifunctional thiol reagent dibromobimane, suggesting that cyclopentenone PG may be directly involved in oligomer formation. Remarkably, Δ12-PGJ2-induced oligomeric species were clearly observed by electron microscopy showing dimensions compatible with GSTP1-1 tetramers. These results provide the first direct visualization of GSTP1-1 oligomeric species. Moreover, they offer novel strategies for the modulation of GSTP1-1 cellular functions, which could be exploited to overcome its role in cancer chemoresistance.

Footnotes

  • This work was supported by the Spanish Ministry of Science and Innovation [Grants SAF-2006-03489, SAF-2009-11642, BFU2008-00666, BFU-2009-08977, SAF-2008-00451]; Instituto de Salud Carlos III [Grants RD07/0064/0007, RD06/0020/1001]; Human Frontiers Science Program [Grant RGP39/2008]; and the Autonomous Region of Madrid [Grant CAM S-BIO-0214-2006].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.065391.

  • ABBREVIATIONS:

    GST
    glutathione transferase
    GSTP1-1
    glutathione transferase isoform P1-1
    JNK
    c-Jun NH2-terminal kinase
    cyPG
    cyclopentenone prostaglandin(s)
    15d-PGJ2
    15-deoxy-Δ12,14-prostaglandin J2
    15d-PGJ2-B
    15d-PGJ2-biotin
    PGA1-B
    PGA1-biotin
    PAGE
    polyacrylamide gel electrophoresis
    HRP
    horseradish peroxidase
    ECL
    enhanced chemiluminescence
    RMC
    rat mesangial cell
    PG
    prostaglandin
    DTT
    dithiothreitol
    PCR
    polymerase chain reaction
    2D
    two-dimensional
    HNE
    4-hydroxy-2-nonenal.

  • Received April 6, 2010.
  • Accepted July 13, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
View Full Text

MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Molecular Pharmacology: 78 (4)
Molecular Pharmacology
Vol. 78, Issue 4
1 Oct 2010
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • 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.
Cyclopentenone Prostaglandins with Dienone Structure Promote Cross-Linking of the Chemoresistance-Inducing Enzyme Glutathione Transferase P1-1
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

Cyclopentenone Prostaglandins with Dienone Structure Promote Cross-Linking of the Chemoresistance-Inducing Enzyme Glutathione Transferase P1-1

Francisco J. Sánchez-Gómez, Beatriz Díez-Dacal, María A. Pajares, Oscar Llorca and Dolores Pérez-Sala
Molecular Pharmacology October 1, 2010, 78 (4) 723-733; DOI: https://doi.org/10.1124/mol.110.065391

Citation Manager Formats

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

Share
Research ArticleArticle

Cyclopentenone Prostaglandins with Dienone Structure Promote Cross-Linking of the Chemoresistance-Inducing Enzyme Glutathione Transferase P1-1

Francisco J. Sánchez-Gómez, Beatriz Díez-Dacal, María A. Pajares, Oscar Llorca and Dolores Pérez-Sala
Molecular Pharmacology October 1, 2010, 78 (4) 723-733; DOI: https://doi.org/10.1124/mol.110.065391
del.icio.us logo Digg logo Reddit logo Twitter 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
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Anti-aromatase activity of exemestane phase II metabolites
  • α-Conotoxin Binding Site on the GABAB Receptor
  • Upacicalcet binds to the amino acid binding site of CaSR
Show more Articles

Similar Articles

Advertisement
  • 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 © 2022 by the American Society for Pharmacology and Experimental Therapeutics