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Molecular Pharmacology

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Research ArticleArticle

Methyl 2-Cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate Is a Peroxisome Proliferator-Activated Receptor-γ Agonist That Induces Receptor-Independent Apoptosis in LNCaP Prostate Cancer Cells

Sabitha Papineni, Sudhakar Chintharlapalli and Stephen Safe
Molecular Pharmacology February 2008, 73 (2) 553-565; DOI: https://doi.org/10.1124/mol.107.041285
Sabitha Papineni
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Sudhakar Chintharlapalli
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Stephen Safe
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Abstract

Methyl 2-cyano-3,11-dioxo-18β-olean-1,12-diene-30-oate (β-CDODA-Me) is a synthetic analog of the naturally occurring triterpenoid glycyrrhetinic acid, which contains a 2-cyano substituent in the A-ring. β-CDODA-Me was a potent inhibitor of LNCaP prostate cancer cell growth (IC50 ∼1 μM) and activated peroxisome proliferator-activated receptor γ (PPARγ), whereas analogs without the cyano group were weakly cytotoxic and did not activate PPARγ. β-CDODA-Me induced p21 and p27, down-regulated cyclin D1 protein expression, and induced two other proapoptotic proteins, namely nonsteroidal anti-inflammatory drug-activated gene-1 and activating transcription factor-3. However, induction of these responses by β-CDODA-Me was PPARγ-independent and due to activation of phosphatidylinositol-3-kinase, mitogen-activated protein kinase, and jun N-terminal kinase pathways by this compound. In contrast, β-CDODA-Me also decreased androgen receptor (AR) and prostate-specific antigen (PSA) mRNA and protein levels through kinase-independent pathways. β-CDODA-Me repressed AR mRNA transcription, whereas decreased PSA mRNA levels were dependent on protein synthesis and were reversed by cycloheximide. Thus, potent inhibition of LNCaP cell survival by β-CDODA-Me is due to PPARγ-independent activation of multiple pathways that selectively activate growth-inhibitory and proapoptotic responses.

Footnotes

  • This work was supported by the National Institutes of Health (ES09106) and the Texas Agricultural Experiment Station.

  • S.P. and S.C. contributed equally to this study.

  • ABBREVIATIONS: PPAR, peroxisome proliferator-activated receptor; PGJ2, 15-deoxy-Δ12,14-prostaglandin J2; TZD, thiazolidinedione; CDDO, 2-cyano-3,12-dioxo-17α-olean-1,9-dien-28-oic acid; C-DIM, 1,1-bis(3′-indolyl)-1-(p-substituted phenyl)methane; GA, glycyrrhetinic acid; β-CDODA-Me, methyl 2-cyano-3,11-dioxo-18β-olean-1,12-diene-30-oate; NAG-1, nonsteroidal anti-inflammatory drug-activated gene 1; AR, androgen receptor; PSA, prostate-specific antigen; T007, N-(4′-aminopyridyl)-2-chloro-5-nitrobenzamide; DIM, 3,3′-diindolylmethane; ATF3, activating transcription factor 3; MAPK, mitogen-activated protein kinase; JNK, c-Jun NH2-terminal kinase; FBS, fetal bovine serum; DMEM, Dulbecco's modified Eagle's medium; DMSO, dimethyl sulfoxide; FACS, fluorescence-activated cell sorting; PCR, polymerase chain reaction; TBST, Tris-buffered saline/Tween 20; EGR-1, early growth response-1; PARP, poly(ADP-ribose) polymerase; DHT, dihydrotestosterone; PI3K, phosphoinositol-3-kinase; NAC, N-acetyl cysteine; PI, propidium iodide; MG132, N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal; PD98059, 2′-amino-3′-methoxyflavone; LY294002, 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride; SP600125, 1,9-pyrazoloanthrone; GF109203X, 3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride.

    • Received August 28, 2007.
    • Accepted November 7, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 73 (2)
Molecular Pharmacology
Vol. 73, Issue 2
1 Feb 2008
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Methyl 2-Cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate Is a Peroxisome Proliferator-Activated Receptor-γ Agonist That Induces Receptor-Independent Apoptosis in LNCaP Prostate Cancer Cells
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Research ArticleArticle

Methyl 2-Cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate Is a Peroxisome Proliferator-Activated Receptor-γ Agonist That Induces Receptor-Independent Apoptosis in LNCaP Prostate Cancer Cells

Sabitha Papineni, Sudhakar Chintharlapalli and Stephen Safe
Molecular Pharmacology February 1, 2008, 73 (2) 553-565; DOI: https://doi.org/10.1124/mol.107.041285

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Research ArticleArticle

Methyl 2-Cyano-3,11-dioxo-18β-olean-1,12-dien-30-oate Is a Peroxisome Proliferator-Activated Receptor-γ Agonist That Induces Receptor-Independent Apoptosis in LNCaP Prostate Cancer Cells

Sabitha Papineni, Sudhakar Chintharlapalli and Stephen Safe
Molecular Pharmacology February 1, 2008, 73 (2) 553-565; DOI: https://doi.org/10.1124/mol.107.041285
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