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.
Highlights
Monoamine 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)
Each increase of 10% in the percent of the tumor classified as grade 4/5 at the time of surgery leads to a 10% increase in the failure rate as measured by detectable and rising serum prostate specific antigen (PSA), a biomarker of prostate cancer (PCa)
We examined the gene expression changes in primary cultures of cancer cells derived from high grade surgical specimens (E-CA cells) in response to clorgyline treatment, and identified two major effects of clorgyline on PCa cells
Summary
Monoamine 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). Cancers composed entirely of Gleason grade 3 (well-differentiated) have a > 95% chance of being cured by surgery. Each increase of 10% in the percent of the tumor classified as grade 4/5 at the time of surgery leads to a 10% increase in the failure rate as measured by detectable and rising serum prostate specific antigen (PSA), a biomarker of prostate cancer (PCa). Despite the accumulating knowledge about the biology of PCa, the molecular machineries that differ between grade 3 and 4/ 5 cancers and mark a critical change from curable to lethal are largely unknown
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