Prostate-specific membrane antigen modulates the progression of prostate cancer by regulating the synthesis of arginine and proline and the expression of androgen receptors and Fos proto-oncogenes

The expression of prostate-specific membrane antigen (PSMA) is strikingly upregulated during oncogenesis and prostate cancer (PCa) progression, but the functions of this antigen in PCa remain unclear. Here, we constructed PSMA-knockdown LNCaP and 22rv1 cell lines and performed metabonomic and transcriptomic analyses to determine the effects of PSMA on PCa metabolism and transcription. The metabolism of arginine and proline was detected using specific kits. The mRNA and protein expression levels of the identified differentially expressed genes were quantified by RT-qPCR and Western blotting. The proliferation of each cell line was evaluated through CCK-8, EdU and colony formation assays. The migration and invasion abilities of each cell line were detected using wound healing and transwell assays, respectively. PSMA knockdown led to metabolic disorder and abnormal transcription in PCa and resulted in inhibition of the proliferation and metastasis of PCa cells in vitro and in vivo. The depletion of PSMA also promoted the biosynthesis of arginine and proline, inhibited the expression of AR and PSA, and induced the expression of c-Fos and FosB. PSMA plays an important role in the metabolism, proliferation and metastasis of human PCa and may be a promising therapeutic target.

前列腺特异性膜抗原（prostate-specific membrane antigen, PSMA）在肿瘤发生及前列腺癌（prostate cancer, PCa）进展过程中呈现显著上调表达，但其在前列腺癌中的具体功能仍未明确。本研究构建了PSMA敲低的LNCaP与22rv1细胞系，并开展代谢组学与转录组学分析，以探究PSMA对前列腺癌代谢与转录的调控作用。研究采用特异性检测试剂盒对精氨酸与脯氨酸的代谢水平进行了检测；通过实时荧光定量PCR（RT-qPCR）与蛋白质免疫印迹（Western blotting）对鉴定得到的差异表达基因的mRNA及蛋白表达水平进行定量检测；采用CCK-8、EdU及平板克隆形成实验评估各细胞系的增殖能力，分别通过划痕愈合实验与Transwell实验检测细胞的迁移与侵袭能力。实验结果显示，PSMA敲低可引发前列腺癌细胞的代谢紊乱与转录异常，并在体外及体内抑制前列腺癌细胞的增殖与转移能力；同时，PSMA敲低还可促进精氨酸与脯氨酸的生物合成，抑制雄激素受体（AR）与前列腺特异性抗原（PSA）的表达，诱导c-Fos与FosB的表达。综上，PSMA在人类前列腺癌的代谢、增殖及转移过程中发挥关键作用，有望成为极具潜力的治疗靶点。