Heston W D
Urologic Oncology Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Urology. 1997 Mar;49(3A Suppl):104-12. doi: 10.1016/s0090-4295(97)00177-5.
We have cloned the gene encoding the prostate-specific membrane (PSM) antigen, which is recognized by the 7E11C-5 antibody. The antigen is strongly expressed in prostate cancer, and the antibody has been approved for use as an imaging agent for detection of prostatic cancer metastasis. The gene was unique and encoded a type II membrane protein. The only clue to its potential function was found in the cDNA coding sequences from 1250 to 1700, which had a modest but significant homology with transferrin-receptor, demonstrating a 54% homology of nucleic acid sequence. In comparing the mRNA obtained from normal prostate with that obtained from cancerous or lymph node carcinoma of the prostate (LNCaP) cells, normal cells produced a shorter alternative spliced species that encoded a cytosolic form of the protein, and not a membrane protein. It appeared that, as the prostatic cells became cancerous, there was a nearly 100-fold difference in expression of the ratio of the messages encoding the 2 forms, with the cytosolic form (PSM') predominant in normal cells and the membrane form (PSM) predominant in cancer cells. The other tissue in which the membrane antigen form of PSM is highly expressed is the membrane brush border of the small intestine of the proximal, but not distal, small intestine. This is the location of a unique membrane form of a folate hydrolase. This membrane folate hydrolase and its location are necessary in human nutrition because humans require folate, and the folate in foods is poly-gamma-glutamated. Polyglutamated folates cannot be taken into the cells by folate-transporter systems. The ability to take up folate from foods requires the membrane folate hydrolase to sequentially remove the gamma-linked glutamates, freeing folate that can then be transported. PSM antigen has a similar folate hydrolase activity. Others have reported finding an enzyme in the rat brain that functions as an alpha-neurocarboxypeptidase and acts on the abundant brain peptide N-acetylaspartylglutamate to generate glutamate and N-acetylaspartate. The 3'-end of the rat brain enzyme had 84% sequence homology with PSM antigen. Because this enzyme liberates glutamate in the brain, the enzyme is considered to have regulatory activity related to glutamate receptors. Current investigations are underway to determine whether glutamate receptors are present in prostate. Thus, PSM antigen is a unique folate hydrolase-carboxypeptidase that can release glutamate with either gamma-or alpha-linkage. Its enzymatic activity raises a number of questions for consideration. In the normal prostate where the protein is intracellular, is PSM' antigen keeping folate in nonglutamated forms? If so, folate should be able to readily diffuse out of prostate cells, making the prostate gland an organ at risk for localized folate deficiency and carcinogenesis. In prostate tumor cells, with the enzyme outside of the cell, can PSM antigen be used for the activation of cytotoxic prodrugs?
我们已经克隆了编码前列腺特异性膜（PSM）抗原的基因，该抗原可被7E11C-5抗体识别。该抗原在前列腺癌中强烈表达，并且该抗体已被批准用作检测前列腺癌转移的成像剂。该基因是独特的，编码一种II型膜蛋白。其潜在功能的唯一线索存在于1250至1700的cDNA编码序列中，该序列与转铁蛋白受体具有适度但显著的同源性，核酸序列同源性为54%。在比较从正常前列腺获得的mRNA与从前列腺癌或前列腺淋巴结癌细胞（LNCaP）获得的mRNA时，正常细胞产生一种较短的可变剪接产物，其编码该蛋白的胞质形式，而非膜蛋白。似乎随着前列腺细胞癌变，编码这两种形式的信使RNA的表达比例存在近100倍的差异，胞质形式（PSM'）在正常细胞中占主导，而膜形式（PSM）在癌细胞中占主导。PSM膜抗原形式高度表达的另一个组织是近端小肠而非远端小肠的小肠膜刷状缘。这是一种独特的叶酸水解酶膜形式的位置。这种膜叶酸水解酶及其位置在人类营养中是必需的，因为人类需要叶酸，而食物中的叶酸是多聚γ-谷氨酸化的。多聚谷氨酸化的叶酸不能通过叶酸转运系统进入细胞。从食物中摄取叶酸的能力需要膜叶酸水解酶依次去除γ-连接的谷氨酸，释放出随后可被转运的叶酸。PSM抗原具有类似的叶酸水解酶活性。其他人报告在大鼠脑中发现一种酶，其作为α-神经羧肽酶发挥作用，作用于丰富的脑肽N-乙酰天冬氨酰谷氨酸以生成谷氨酸和N-乙酰天冬氨酸。大鼠脑酶的3'端与PSM抗原具有84%的序列同源性。由于这种酶在脑中释放谷氨酸，可以认为该酶具有与谷氨酸受体相关的调节活性。目前正在进行研究以确定前列腺中是否存在谷氨酸受体。因此，PSM抗原是一种独特的叶酸水解酶-羧肽酶，能够释放γ-或α-连接的谷氨酸。其酶活性引发了许多值得考虑的问题。在蛋白质位于细胞内的正常前列腺中，PSM'抗原是否将叶酸保持在非谷氨酸化形式？如果是这样，叶酸应该能够很容易地从前列腺细胞中扩散出来，使前列腺成为有局部叶酸缺乏和致癌风险的器官。在前列腺肿瘤细胞中，由于酶在细胞外，PSM抗原能否用于激活细胞毒性前药？
