Received for publication August 28, 2007.
Revised November 7, 2007.
Accepted for publication November 7, 2007.

Methyl 2-Cyano-3,11-Dioxo-18-Olean-1,12-Dien-30-Oate Is A Peroxisome Proliferator-Activated Receptor Agonist That Induces Receptor-Independent Apoptosis In LNCaP Prostate Cancer Cells

Abstract

Methyl 2-cyano-3,11-dioxo-18-olean-1,12-diene-30-oate (-CDODA-Me) is a synthetic analog of the naturally-occurring triterpenoid glycyrrhetinic acid which contains a 2-cyano substituent in the A-ring. -CDODA-Me was a potent inhibitor of LNCaP prostate cancer cell growth (IC₅₀ ~ 1 µM) and activated peroxisome proliferator-activated receptor (PPAR), whereas analogs without the cyano group were weakly cytotoxic and did not activate PPAR. -CDODA-Me induced p21 and p27 and downregulated cyclin D1 protein expression and also induced two other proapoptotic proteins, namely nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) and activating transcription factor-3 (ATF-3). However, induction of these responses by -CDODA-Me was PPAR-independent and due to activation of phosphatidylinositol-3-kinase (PI3K), mitogen activated protein kinase (MAPK), and jun N-terminal kinase (JNK) pathways by this compound. In contrast, -CDODA-Me also decreased androgen receptor (AR) and prostate specific antigen (PSA) mRNA and protein levels through kinase-independent pathways. -CDODA-Me repressed AR mRNA transcription, whereas decreased PSA mRNA levels were dependent on protein synthesis and was reversed by cycloheximide. Thus, potent inhibition of LNCaP cell survival by -CDODA-Me is due to PPAR-independent activation of multiple pathways that selectively activate growth inhibitory and proapoptotic responses.

Key words: PPARs, Structure-activity relationships and modeling, Receptor binding studies, Receptor-mediated, Protein-binding, Regulation - transcriptional, Structure/function/mechanism, Apoptosis, Mechanisms of cell killing/apoptosis, Transcription targets