Inhibition of monoamine oxidase A promotes secretory differentiation in basal prostatic epithelial cells

Abstract

Monoamine oxidase A (MAO-A) expression is associated with high-grade prostate cancer. Immunohistochemistry showed that MAO-A is also expressed in the basal epithelial cells of normal prostate glands. Using cultured primary prostatic epithelial cells as a model, we showed that MAO-A prevents basal epithelial cells from differentiating into secretory cells. Under differentiationpromoting conditions, clorgyline, an irreversible MAO-A inhibitor, induced secretory cell-like morphology and repressed expression of cytokeratin 14, a basal cell marker. More importantly, clorgyline induced mRNA and protein expression of androgen receptor (AR), a hallmark of secretory epithelial cells. In clorgyline-treated cells, androgen induced luciferase activity controlled by the promoter of prostate-specific antigen, an AR target gene, in a dose-dependent manner. This activity was blocked by the AR antagonist Casodex, showing that AR is functional. In turn, androgen decreased MAO-A expression in clorgyline-treated, secretory-like cells. Our results demonstrated that cultured basal epithelial cells have the potential to differentiate into secretory cells, and that inhibition of MAO-A is a key factor in promoting this process. Increased expression of MAO-A in high-grade prostate cancer may be an important contributor to its de-differentiated phenotype, raising the possibility that MAO-A inhibition may restore differentiation and reverse the aggressive behavior of high-grade cancer.

Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis

“…We observed both increased MAOA expression and EMT in the same specimens of high-grade PCa, which, in line with our other results showing that MAOA can drive EMT (Figure 1), provides a molecular basis for the acquisition of a more aggressive phenotype in high-Gleason grade PCa. Our observation is consistent with previous studies showing that pharmacological inhibition of MAOA in PCa cells kept basal prostatic epithelial cells from differentiating into matured glandular structures by reorganizing cell structures and decreasing the expression of basal cytokeratins (9). In addition, a recent clinical survey assessing EMT marker levels in clinical samples with organ-confined PCa revealed that vimentin and TWIST1, among 13 other EMT markers, showed the most promising predictive potential for poor prognosis including biochemical recurrence (57).…”

“…Recently, a significant correlation was established between increased levels of MAOA expression and high Gleason grade or poorly differentiated human prostate tumors (7,8). MAOA is exclusively expressed in the epithelial cells of prostatic glands with relatively low levels in stromal counterparts (9). These observations collectively suggest that MAOA may function in an autocrine manner to regulate the proliferation and differentiation of prostatic epithelial cells.…”

E-cadherin-mediated survival of androgen-receptor-expressing secretory prostate epithelial cells derived from a stratified in vitro differentiation model

“…By confocal imaging, some of them appear to have formed a hollow mound (data not shown). A recent study demonstrated that co-treatment of prostate basal cells with the monoamine oxidase A inhibitor clorgyline, 1,25-dihydroxyvitamin D 3 , all-trans retinoic acid and TGF-1 induced AR expression and loss of basal marker K14 (Zhao et al, 2008), suggesting that there might be alternative mechanisms to inducing prostate epithelial cell differentiation.In contrast to other published systems, we have demonstrated that our model can be utilized for biochemical and genetic manipulation. It is amenable to treatment with pharmacological inhibitors or siRNA to study signaling and biological pathways.…”

Exploiting a Molecular Gleason Grade for Prostate Cancer Therapy

“…Subsequent studies demonstrated that MAOA inhibits prostate cell differentiation (28), and the MAOA inhibitor clorgyline is capable of suppressing pro-oncogenic programs in prostate cancer cells (29).…”

“…Task 15: Repeat Tasks 10-13 for two additional proteins (months [24][25][26][27][28][29][30][31][32][33][34]. Due to the failure of ELISA specificity, we evaluated the Luminex system for the utilization of single- Figure 4.…”