Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • 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
  • 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
    • 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
  • Visit molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Research ArticleArticle

The Phosphoinositide-Dependent Kinase-1 Inhibitor 2-Amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide (OSU-03012) Prevents Y-Box Binding Protein-1 from Inducing Epidermal Growth Factor Receptor

K. To, Y. Zhao, H. Jiang, K. Hu, M. Wang, J. Wu, C. Lee, D. W. Yokom, A. L. Stratford, U. Klinge, P. R. Mertens, C. S. Chen, M. Bally, D. Yapp and S. E. Dunn
Molecular Pharmacology September 2007, 72 (3) 641-652; DOI: https://doi.org/10.1124/mol.107.036111
K. To
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Y. Zhao
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
H. Jiang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
K. Hu
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
M. Wang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
J. Wu
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
C. Lee
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
D. W. Yokom
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
A. L. Stratford
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
U. Klinge
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
P. R. Mertens
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
C. S. Chen
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
M. Bally
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
D. Yapp
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
S. E. Dunn
  • 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

This article has corrections. Please see:

  • Correction to “The Phosphoinositide-Dependent Kinase-1 Inhibitor 2-Amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide (OSU-03012) Prevents Y-Box Binding Protein-1 from Inducing Epidermal Growth Factor Receptor” - March 01, 2014
  • Re: To K, Zhao Y, Jiang H, Hu K, Wang M, Wu J, Lee C, Yokom DW, Stratford AL, Klinge U, Mertens PR, Chen CS, Bally M, Yapp D, and Dunn SE (2007) The Phosphoinositide-Dependent Kinase-1 Inhibitor 2-Amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide (OSU-03012) Prevents Y-Box Binding Protein-1 from Inducing Epidermal Growth Factor Receptor. Mol Pharmacol 72:641-652; doi:10.1124/mol.107.036111 - July 01, 2016

Abstract

The epidermal growth factor receptor (EGFR) is integral to basal-like and human epidermal growth factor receptor-2 (Her-2)-overexpressing breast cancers. Such tumors are associated with poor prognosis, the majority of which express high levels of EGFR. We reported that EGFR expression is induced by the oncogenic transcription factor Y-box binding protein-1 (YB-1) that occurs in a manner dependent on phosphorylation by Akt. Herein, we questioned whether blocking Akt with 2-amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide (OSU-03012), a phosphoinositide-dependent protein kinase-1 (PDK-1) small-molecule inhibitor, could prevent YB-1 from binding to the EGFR promoter. MDA-MB-468 and SUM 149 are basal-like breast cancer (BLBC) cells that were used for our studies because they express high levels of activated PDK-1, YB-1, and EGFR compared with the immortalized breast epithelial cell line 184htrt. In these cell lines, YB-1 preferentially bound to the –1 kilobase of the EGFR promoter, whereas this did not occur in the 184htrt cells based on chromatin immunoprecipitation. When the cells were exposed to OSU-03012 for 6 h, YB-1/EGFR promoter binding was significantly attenuated. To further confirm this observation, gel-shift assays showed that the drug inhibits YB-1/EGFR promoter binding. The inhibitory effect of OSU-03012 on EGFR was also observed at the mRNA and protein levels. OSU-03012 ultimately inhibited the growth of BLBC in monolayer and soft agar coordinate with the induction of apoptosis using an Array-Scan VTI high-content screening system. Furthermore, OSU-03012 inhibited the expression of EGFR by 48% in tumor xenografts derived from MDA-MB-435/Her-2 cells. This correlated with loss of YB-1 binding to the EGFR promoter. Hence, we find that OSU-03012 inhibits YB-1 resulting in a loss of EGFR expression in vitro and in vivo.

Footnotes

  • This research was supported by grants through the Canadian Breast Cancer Research Alliance, the National Cancer Institute of Canada, and Rethink Breast Cancer (to S.E.D.). Additional funds were provided by SFB542 (to P.R.M.).

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

  • doi:10.1124/mol.107.036111.

  • ABBREVIATIONS: Her-2, human epidermal growth factor receptor-2; BLBC, basal-like breast cancer; ChIP, chromatin immunoprecipitation; EGFR, epidermal growth factor receptor; ER, estrogen receptor; PDK-1, phosphoinositide-dependent protein kinase-1; PR, progesterone receptor; PCNA, proliferating nuclear antigen; TOPO-II, topoisomerase II; YB-1, Y-box binding protein-1; PBS, phosphate-buffered saline; PBST, phosphate-buffered saline/Tween; siRNA, small interfering RNA; RT, room temperature; PI, propidium iodide; FITC, fluorescein isothiocyanate; ARE, AU-rich element; BSA, bovine serum albumin; kb, kilobase; DMSO, dimethyl sulfoxide; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PCR, polymerase chain reaction; OSU-03012, 2-amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide; OGX-011, DNA, d(P-thio)((2′-O-(2-methoxyethyl))m5rC-(2′-O-(2-methoxyethyl))rA-(2′-O-(2-methoxyethyl))rG-(2′-O-(2-methoxyethyl))-m5rC-A-G-C-A-G-A-G-T-C-T-T-C-A-(2′-O-(2-methoxyethyl))m5rU-(2′-O-(2-methoxyethyl))m5rC-(2′-O-(2-methoxyethyl))rA-(2′-O-(2-methoxy-ethyl))m5rU); HCS, high-content screening.

    • Received March 14, 2007.
    • Accepted June 26, 2007.
  • 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: 72 (3)
Molecular Pharmacology
Vol. 72, Issue 3
1 Sep 2007
  • 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.
The Phosphoinositide-Dependent Kinase-1 Inhibitor 2-Amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide (OSU-03012) Prevents Y-Box Binding Protein-1 from Inducing Epidermal Growth Factor Receptor
(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

The Phosphoinositide-Dependent Kinase-1 Inhibitor 2-Amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide (OSU-03012) Prevents Y-Box Binding Protein-1 from Inducing Epidermal Growth Factor Receptor

K. To, Y. Zhao, H. Jiang, K. Hu, M. Wang, J. Wu, C. Lee, D. W. Yokom, A. L. Stratford, U. Klinge, P. R. Mertens, C. S. Chen, M. Bally, D. Yapp and S. E. Dunn
Molecular Pharmacology September 1, 2007, 72 (3) 641-652; DOI: https://doi.org/10.1124/mol.107.036111

Citation Manager Formats

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

The Phosphoinositide-Dependent Kinase-1 Inhibitor 2-Amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide (OSU-03012) Prevents Y-Box Binding Protein-1 from Inducing Epidermal Growth Factor Receptor

K. To, Y. Zhao, H. Jiang, K. Hu, M. Wang, J. Wu, C. Lee, D. W. Yokom, A. L. Stratford, U. Klinge, P. R. Mertens, C. S. Chen, M. Bally, D. Yapp and S. E. Dunn
Molecular Pharmacology September 1, 2007, 72 (3) 641-652; DOI: https://doi.org/10.1124/mol.107.036111
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
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Editing TOP2α Intron 19 5′ SS Circumvents Drug Resistance
  • CTS Bias
  • Positive allosteric modulation of the mGlu5 receptor
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 © 2021 by the American Society for Pharmacology and Experimental Therapeutics