Inhibition of monoamine oxidase A promotes secretory differentiation in basal prostatic epithelial cells.
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 differentiation-promoting 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.
Zhao
Hongjuan
H
Department of Urology Stanford University School of Medicine 300 Pasteur Drive, Grant Building S227 MC 5118, Stanford, CA 94305, USA.
Nolley
Rosalie
R
Chen
Zuxiong
Z
Reese
Stephen W
SW
Peehl
Donna M
DM
D002454:Cell Differentiation; D003010:Clorgyline / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010641:Phenotype; D011467:Prostate / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism
D008996:Monoamine Oxidase Inhibitors; D011944:Receptors, Androgen; D008995:Monoamine Oxidase; D017430:Prostate-Specific Antigen; D003010:Clorgyline