Skip to main content
  • AACR Journals
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Focus on Radiation Oncology
      • Novel Combinations
      • Reviews
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

  • AACR Journals
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Focus on Radiation Oncology
      • Novel Combinations
      • Reviews
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

Research Articles: Therapeutics, Targets, and Development

Mitogen-activated protein kinase kinase 1/2 inhibitors and 17-allylamino-17-demethoxygeldanamycin synergize to kill human gastrointestinal tumor cells in vitro via suppression of c-FLIP-s levels and activation of CD95

Margaret A. Park, Guo Zhang, Clint Mitchell, Mohamed Rahmani, Hossein Hamed, Michael P. Hagan, Adly Yacoub, David T. Curiel, Paul B. Fisher, Steven Grant and Paul Dent
Margaret A. Park
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Guo Zhang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Clint Mitchell
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mohamed Rahmani
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hossein Hamed
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael P. Hagan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Adly Yacoub
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David T. Curiel
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul B. Fisher
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Steven Grant
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul Dent
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1158/1535-7163.MCT-08-0400 Published September 2008
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Prior studies have noted that inhibitors of mitogen-activated protein kinase (MAPK) kinase 1/2 (MEK1/2) enhanced geldanamycin lethality in malignant hematopoietic cells by promoting mitochondrial dysfunction. The present studies focused on defining the mechanism(s) by which these agents altered survival in carcinoma cells. MEK1/2 inhibitors [PD184352; AZD6244 (ARRY-142886)] interacted in a synergistic manner with geldanamycins [17-allylamino-17-demethoxygeldanamycin (17AAG) and 17-dimethylaminoethylamino-17-demethoxy-geldanamycin] to kill hepatoma and pancreatic carcinoma cells that correlated with inactivation of extracellular signal-regulated kinase 1/2 and AKT and with activation of p38 MAPK; p38 MAPK activation was reactive oxygen species dependent. Treatment of cells with MEK1/2 inhibitors and 17AAG reduced expression of c-FLIP-s that was mechanistically connected to loss of MEK1/2 and AKT function; inhibition of caspase-8 or overexpression of c-FLIP-s abolished cell killing by MEK1/2 inhibitors and 17AAG. Treatment of cells with MEK1/2 inhibitors and 17AAG caused a p38 MAPK-dependent plasma membrane clustering of CD95 without altering the levels or cleavage of FAS ligand. In parallel, treatment of cells with MEK1/2 inhibitors and 17AAG caused a p38 MAPK-dependent association of caspase-8 with CD95. Inhibition of p38 MAPK or knockdown of BID, FAS-associated death domain, or CD95 expression suppressed MEK1/2 inhibitor and 17AAG lethality. Similar correlative data were obtained using a xenograft flank tumor model system. Our data show that treatment of tumor cells with MEK1/2 inhibitors and 17AAG induces activation of the extrinsic pathway and that suppression of c-FLIP-s expression is crucial in transduction of the apoptotic signal from CD95 to promote cell death. [Mol Cancer Ther 2008;7(9):2633–48]

Keywords:
  • CD95
  • caspase
  • extrinsic
  • FLIP

Footnotes

  • ↵6 Supplementary materials for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • ↵7 Unpublished findings.

  • Grant support: USPHS grants R01-DK52825, P01-CA104177, and R01-CA108325 and The Jim Valvano “V” Foundation (P. Dent); USPHS grants R01-CA63753 and R01-CA77141 and Leukemia Society of America grant 6405-97 (S. Grant); USPHS grants P01-CA104177, R01-CA097318, R01-CA098172, and P01-NS031492 and The Samuel Waxman Cancer Research Foundation (P.B. Fisher); and USPHS grant P01-CA104177 (D.T. Curiel). P. Dent is The Universal, Inc., Professor in Signal Transduction Research and P.B. Fisher is a Samuel Waxman Cancer Research Foundation investigator.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • Note: M.A. Park and G. Zhang contributed equally to the execution and completion of these studies.

    • Accepted June 9, 2008.
    • Received April 24, 2008.
    • Revision received June 9, 2008.
  • American Association for Cancer Research
View Full Text
PreviousNext
Back to top
Molecular Cancer Therapeutics: 7 (9)
September 2008
Volume 7, Issue 9
  • Table of Contents
  • About the Cover

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Cancer Therapeutics 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.
Mitogen-activated protein kinase kinase 1/2 inhibitors and 17-allylamino-17-demethoxygeldanamycin synergize to kill human gastrointestinal tumor cells in vitro via suppression of c-FLIP-s levels and activation of CD95
(Your Name) has forwarded a page to you from Molecular Cancer Therapeutics
(Your Name) thought you would be interested in this article in Molecular Cancer Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Mitogen-activated protein kinase kinase 1/2 inhibitors and 17-allylamino-17-demethoxygeldanamycin synergize to kill human gastrointestinal tumor cells in vitro via suppression of c-FLIP-s levels and activation of CD95
Margaret A. Park, Guo Zhang, Clint Mitchell, Mohamed Rahmani, Hossein Hamed, Michael P. Hagan, Adly Yacoub, David T. Curiel, Paul B. Fisher, Steven Grant and Paul Dent
Mol Cancer Ther September 1 2008 (7) (9) 2633-2648; DOI: 10.1158/1535-7163.MCT-08-0400

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Mitogen-activated protein kinase kinase 1/2 inhibitors and 17-allylamino-17-demethoxygeldanamycin synergize to kill human gastrointestinal tumor cells in vitro via suppression of c-FLIP-s levels and activation of CD95
Margaret A. Park, Guo Zhang, Clint Mitchell, Mohamed Rahmani, Hossein Hamed, Michael P. Hagan, Adly Yacoub, David T. Curiel, Paul B. Fisher, Steven Grant and Paul Dent
Mol Cancer Ther September 1 2008 (7) (9) 2633-2648; DOI: 10.1158/1535-7163.MCT-08-0400
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
    • Disclosure of Potential Conflicts of Interest
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma
  • Effective sensitization of temozolomide by ABT-888 is lost with development of temozolomide resistance in glioblastoma xenograft lines
  • Effect of hypoxia on the expression of phosphoglycerate kinase and antitumor activity of troxacitabine and gemcitabine in non-small cell lung carcinoma
Show more Research Articles: Therapeutics, Targets, and Development
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook  Twitter  LinkedIn  YouTube  RSS

Articles

  • Online First
  • Current Issue
  • Past Issues
  • Meeting Abstracts

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About MCT

  • About the Journal
  • Editorial Board
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Molecular Cancer Therapeutics
eISSN: 1538-8514
ISSN: 1535-7163

Advertisement