Inhibition of monoamine oxidase A promotes secretory differentiation in basal prostatic epithelial cells
Inhibition of monoamine oxidase A promotes secretory differentiation in basal prostatic epithelial cells
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DOI：
10.1111/j.1432-0436.2007.00263.x
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发表时间：
2008-09-01
期刊：
影响因子：
2.9
通讯作者：
Peehl, Donna M.
中科院分区：
文献类型：
--
作者：
Zhao, Hongjuan;Nolley, Rosalie;Peehl, Donna M.
单胺氧化酶A（MAO-A）表达与高级别前列腺癌相关。免疫组化显示MAO-A在正常前列腺基底上皮细胞中也有表达。使用培养的原代前列腺上皮细胞作为模型，我们发现MAO-A阻止基底上皮细胞分化为分泌细胞。在促进分化的条件下，clorgyline，一种不可逆的单胺氧化酶-A抑制剂，诱导分泌细胞样形态和抑制表达的细胞角蛋白14，基底细胞标志物。更重要的是，氯吉林诱导雄激素受体（AR）的mRNA和蛋白质表达，这是分泌性上皮细胞的标志。在氯吉林处理的细胞中，雄激素诱导的荧光素酶活性由前列腺特异性抗原（AR靶基因）的启动子控制，呈剂量依赖性。这种活性被AR拮抗剂Casodex阻断，表明AR是功能性的。反过来，雄激素降低单胺氧化酶-A的表达氯吉林处理，分泌样细胞。我们的研究结果表明，培养的基底上皮细胞具有分化为分泌细胞的潜力，而MAO-A的抑制是促进这一过程的关键因素。高级别前列腺癌中MAO-A表达的增加可能是其去分化表型的重要贡献者，提高了MAO-A抑制可能恢复分化并逆转高级别癌症的侵袭行为的可能性。
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.