Targeting monoamine oxidase A in advanced prostate cancer
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Inhibitors of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades neurotransmitters including serotonin and norepinephrine, are commonly used to treat neurological conditions including depression. Recently, we and others identified high expression of MAOA in normal basal prostatic epithelium and high-grade primary prostate cancer (PCa). In contrast, MAOA is low in normal secretory prostatic epithelium and low-grade PCa. An irreversible inhibitor of MAOA, clorgyline, induced secretory differentiation in primary cultures of normal basal epithelial cells and high-grade PCa. Furthermore, clorgyline inhibited several oncogenic pathways in PCa cells, suggesting clinical value of MAOA inhibitors as a pro-differentiation and anti-oncogenic therapy for high-risk PCa. Here, we extended our studies to a model of advanced PCa, VCaP cells, which were derived from castration-resistant metastatic PCa and express a high level of MAOA.
Growth of VCaP cells in the presence or absence of clorgyline was evaluated in vitro and in vivo. Gene expression changes in response to clorgyline were determined by microarray and validated by quantitative real-time polymerase chain reaction.
Treatment with clorgyline in vitro inhibited growth and altered the transcriptional pattern of VCaP cells in a manner consistent with the pro-differentiation and anti-oncogenic effects seen in treated primary PCa cells. Src, beta-catenin, and MAPK oncogenic pathways, implicated in androgen-independent growth and metastasis, were significantly downregulated. Clorgyline treatment of mice bearing VCaP xenografts slowed tumor growth and induced transcriptome changes similar to those noted in vitro.
Our results support the possibility that anti-depressant drugs that target MAOA might find a new application in treating PCa.
KeywordsProstate cancer Monoamine oxidase Differentiation Oncogenes Androgen
Dr. Flamand was supported by an Association Francaise d’Urologie Fellowship. Dr. Zhao is supported by the National Cancer Institute (Grant number 1 K01 CA123532). Dr. Peehl is supported by the National Cancer Institute (1 R01 CA121460) and a Challenge Award from the Prostate Cancer Foundation. The authors thank Sarah Young and Zuxiong Chen for technical assistance.
Conflict of interest statement
We declare that we have no conflict of interest.
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