MAOA 在诱导前列腺癌神经内分泌分化中的作用

摘要:目的 建立神经内分泌性前列腺癌( neuroendocrine prostate cancer,NEPC) 细胞模型和动物模型,探讨单胺氧化酶 A( monoamine oxidase A,MAOA)在前列腺癌神经内分泌分化( neuroendocrine transdifferentiation,NED) 中的作用及机制。 方法 选取人前列腺癌细胞系 C4-2,通过恩杂鲁胺( enzalutamide,ENZ)长期诱导获得 NEPC 细胞模型;通过酶活性实验、Real-time PCR 和 Western blot 技术检测 NED 过程中 MAOA 的水平变化;使用 MAOA 抑制剂氯吉灵( clorgyline,CLG)检测 MAOA 对神经内分泌标志物的影响并探讨其潜在机制;建立前列腺癌异种移植模型,体内实验验证 MAOA 与 NED 之间的相关性。 结果 ENZ 可作为诱导 NEPC 模型的方法;在 ENZ 引起的 NED 过程中,MAOA 的表达和活性增加;抑制 MAOA 的活性可以延缓 NED 的发生,这可能是 MAOA 通过抑制缺氧信号实现的。结论 MAOA 是促进 NED 和维持神经内分泌细胞特性的关键靶点,MAOA 抑制剂 CLG 可以延缓 NEPC 发生,可能作为前列腺癌患者的潜在治疗药物。

The Function of MAOA in Inducing the Neuroendocrine Differentiation of Prostate Cancer

Abstract: Objective The cell and animal model of neuroendocrine prostate cancer ( NEPC ) were establishedrespectively to explore the function and mechanism of monoamine Oxidase A ( MAOA ) in the neuroendocrine transdifferentiation ( NED ) of prostate cancer ( PCa ) . Method Human prostate cancer cell lines C4-2 were selected to establish the cell model of NEPC by long-term induction of Enzalutamide ( ENZ) treatment. The change of MAOA expression was detected by the enzyme activity experiment, and the marker of neuroendocrine differentiation were analyzed by Real-time fluorescent quantitative PCR and Western blot technology. The PCa cells 22RV1 were implanted subcutaneously into nude mice to establish xenograft model and to observe the effect of MAOA inhibitor clorgyline ( CLG) on neuroendocrine markers, to explore its underlying mechanism. Result ENZ could be used to induce the NEPC cell model. During the process of NED, the expression and activity of MAOA was increased. When CLG inhibit the activity of MAOA in the NEPC animal model the process of NED was delayed. The reason may be MAOA suppression of hypoxia relative signal. Conclusion MAOA is a key target to promote NED and maintain the characteristics of neuroendocrine cells. MAOA inhibitor CLG could delay the occurrence of NEPC and may be a new potential therapeutic drug for prostate cancer patients.