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Research ArticleArticle

Methyl 2-Cyano-3,12-dioxooleana-1,9-dien-28-oate Decreases Specificity Protein Transcription Factors and Inhibits Pancreatic Tumor Growth: Role of MicroRNA-27a

Indira Jutooru, Gayathri Chadalapaka, Maen Abdelrahim, Md Riyaz Basha, Ismael Samudio, Marina Konopleva, Michael Andreeff and Stephen Safe
Molecular Pharmacology August 2010, 78 (2) 226-236; DOI: https://doi.org/10.1124/mol.110.064451
Indira Jutooru
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Gayathri Chadalapaka
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Maen Abdelrahim
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Md Riyaz Basha
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Ismael Samudio
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Marina Konopleva
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Michael Andreeff
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Stephen Safe
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This article has a correction. Please see:

  • Correction to “Methyl 2-Cyano-3,12-dioxooleana-1, 9-dien-28-oate Decreases Specificity Protein Transcription Factors and Inhibits Pancreatic Tumor Growth: Role of MicroRNA-27a” - February 01, 2011

Abstract

The anticancer agent 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its methyl ester (CDDO-Me) typically induce a broad spectrum of growth-inhibitory, proapoptotic, and antiangiogenic responses. Treatment of Panc1, Panc28, and L3.6pL pancreatic cancer cells with low micromolar concentrations of CDDO or CDDO-Me resulted in growth inhibition, induction of apoptosis, and down-regulation of cyclin D1, survivin, vascular endothelial growth factor (VEGF), and its receptor (VEGFR2). RNA interference studies indicate that these repressed genes are regulated by specificity protein (Sp) transcription factors Sp1, Sp3, and Sp4, and Western blot analysis of lysates from pancreatic cancer cells treated with CDDO and CDDO-Me shows for the first time that both compounds decreased the expression of Sp1, Sp3, and Sp4. Moreover, CDDO-Me (7.5 mg/kg/day) also inhibited pancreatic human L3.6pL tumor growth and down-regulated Sp1, Sp3, and Sp4 in tumors using an orthotopic pancreatic cancer model. CDDO-Me also induced reactive oxygen species (ROS) and decreased mitochondrial membrane potential (MMP) in Panc1 and L3.6pL cells, and cotreatment with antioxidants (glutathione and dithiothreitol) blocked the formation of ROS, reversed the loss of MMP, and inhibited down-regulation of Sp1, Sp3, and Sp4. Repression of Sp and Sp-dependent genes by CDDO-Me was due to the down-regulation of microRNA-27a and induction of zinc finger and BTB domain containing 10 (ZBTB10), an Sp repressor, and these responses were also reversed by antioxidants. Thus, the anticancer activity of CDDO-Me is due, in part, to activation of ROS, which in turn targets the microRNA-27a:ZBTB10-Sp transcription factor axis. This results in decreased expression of Sp-regulated genes, growth inhibition, induction of apoptosis, and antiangiogenic responses.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This study was supported by the National Institutes of Health National Cancer Institute [Grants R01-CA108718, P20-CA10193, and R01-CA136571]; and Texas A&M AgriLife Research.

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

    doi:10.1124/mol.110.064451.

  • ABBREVIATIONS:

    CDDO
    2-cyano-3,12-dioxoleana-1,9-dien-28-oic acid
    CDDO-IM
    imidazole ester of 2-cyano-3,12-dioxoleana-1,9-dien-28-oic acid
    CDDO-Me
    methyl ester of 2-cyano-3,12-dioxoleana-1,9-dien-28-oic acid
    CDODA
    2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oic acid
    CDODA-Me
    methyl ester of 2-cyano-3,11-dioxo-18β-olean-1,12-dien-30-oic acid
    GSH
    glutathione
    MMP
    mitochondrial membrane potential
    PPARγ
    peroxisome proliferator-activated receptor γ
    ROS
    reactive oxygen species
    Sp
    specificity protein
    VEGF
    vascular endothelial growth factor
    DMEM
    Dulbecco’s modified Eagle’s medium
    FBS
    fetal bovine serum
    PARP
    poly(ADP-ribose) polymerase
    TBP
    TATA binding protein
    ZBTB10
    zinc finger and BTB domain containing 10
    PCR
    polymerase chain reaction
    DMSO
    dimethyl sulfoxide
    TBST
    Tris-buffered saline/Tween 20
    MG132
    N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal
    DTT
    dithiothreitol
    as-miR-27a
    antisense microRNA-27a
    CM-H2DCFDA
    5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate acetyl ester.

  • Received March 2, 2010.
  • Accepted May 13, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (2)
Molecular Pharmacology
Vol. 78, Issue 2
1 Aug 2010
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Research ArticleArticle

Methyl 2-Cyano-3,12-dioxooleana-1,9-dien-28-oate Decreases Specificity Protein Transcription Factors and Inhibits Pancreatic Tumor Growth: Role of MicroRNA-27a

Indira Jutooru, Gayathri Chadalapaka, Maen Abdelrahim, Md Riyaz Basha, Ismael Samudio, Marina Konopleva, Michael Andreeff and Stephen Safe
Molecular Pharmacology August 1, 2010, 78 (2) 226-236; DOI: https://doi.org/10.1124/mol.110.064451

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Research ArticleArticle

Methyl 2-Cyano-3,12-dioxooleana-1,9-dien-28-oate Decreases Specificity Protein Transcription Factors and Inhibits Pancreatic Tumor Growth: Role of MicroRNA-27a

Indira Jutooru, Gayathri Chadalapaka, Maen Abdelrahim, Md Riyaz Basha, Ismael Samudio, Marina Konopleva, Michael Andreeff and Stephen Safe
Molecular Pharmacology August 1, 2010, 78 (2) 226-236; DOI: https://doi.org/10.1124/mol.110.064451
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