Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cellsReport as inadecuate




Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells - Download this document for free, or read online. Document in PDF available to download.

BMC Medical Genomics

, 2:55

First Online: 20 August 2009Received: 25 July 2008Accepted: 20 August 2009

Abstract

BackgroundMonoamine oxidase A MAO-A, a mitochondrial enzyme that degrades monoamines including neurotransmitters, is highly expressed in basal cells of the normal human prostatic epithelium and in poorly differentiated Gleason grades 4 and 5, aggressive prostate cancer PCa. Clorgyline, an MAO-A inhibitor, induces secretory differentiation of normal prostate cells. We examined the effects of clorgyline on the transcriptional program of epithelial cells cultured from high grade PCa E-CA.

MethodsWe systematically assessed gene expression changes induced by clorgyline in E-CA cells using high-density oligonucleotide microarrays. Genes differentially expressed in treated and control cells were identified by Significance Analysis of Microarrays. Expression of genes of interest was validated by quantitative real-time polymerase chain reaction.

ResultsThe expression of 156 genes was significantly increased by clorgyline at all time points over the time course of 6 – 96 hr identified by Significance Analysis of Microarrays SAM. The list is enriched with genes repressed in 7 of 12 oncogenic pathway signatures compiled from the literature. In addition, genes downregulated ≥ 2-fold by clorgyline were significantly enriched with those upregulated by key oncogenes including beta-catenin and ERBB2, indicating an anti-oncogenic effect of clorgyline. Another striking effect of clorgyline was the induction of androgen receptor AR and classic AR target genes such as prostate-specific antigen together with other secretory epithelial cell-specific genes, suggesting that clorgyline promotes differentiation of cancer cells. Moreover, clorgyline downregulated EZH2, a critical component of the Polycomb Group PcG complex that represses the expression of differentiation-related genes. Indeed, many genes in the PcG repression signature that predicts PCa outcome were upregulated by clorgyline, suggesting that the differentiation-promoting effect of clorgyline may be mediated by its downregulation of EZH2.

ConclusionOur results suggest that inhibitors of MAO-A, already in clinical use to treat depression, may have potential application as therapeutic PCa drugs by inhibiting oncogenic pathway activity and promoting differentiation.

AbbreviationsARandrogen receptor

E-CAhuman prostatic cancer cells

EGFepidermal growth factor

MAO-Amonoamine oxidase A

PCaprostate cancer

PcGPolycomb Group

PSAprostate specific antigen

PSMAprostate specific membrane antigen

qRT-PCRquantitative Real-Time Reverse Transcription Polymerase Chain Reaction

SAMsignificance analysis of microarrays

SMDStanford Microarray Database

TGFtransforming growth factor

VRTR10 nM 1,25-dihydroxyvitamin D3, 1 μM all-trans retinoic acid, 1 ng-ml transforming growth factor TGF-β1, and 1 nM R1881

Electronic supplementary materialThe online version of this article doi:10.1186-1755-8794-2-55 contains supplementary material, which is available to authorized users.

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Author: Hongjuan Zhao - Vincent Flamand - Donna M Peehl

Source: https://link.springer.com/







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