Preferential production of latent transforming growth factor β-2 by primary prostatic epithelial cells and its activation by prostate-specific antigen
Preferential production of latent transforming growth factor β-2 by primary prostatic epithelial cells and its activation by prostate-specific antigen
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DOI：
10.1002/jcp.20147
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发表时间：
2005-02-01
影响因子：
5.6
通讯作者：
Bonewald, LF
中科院分区：
文献类型：
--
作者：
Dallas, SL;Zhao, S;Bonewald, LF
已知的三种哺乳动物转化生长因子- β (TGFbeta)亚型TGFbeta1、2和3在发育过程中具有不重叠的功能。然而，它们在前列腺癌等癌症中的具体作用尚不清楚。在这里，我们发现前列腺上皮细胞的原代培养优先产生和激活潜伏的TGFP2亚型。来自前列腺癌患者的正常和恶性前列腺细胞配对培养主要产生TGFP2亚型，TGFbeta1亚型少30- 70倍。通过单q离子交换色谱法，观察到已知的小潜伏TGFbeta2复合物、已知的大潜伏TGFbeta2复合物和一个新的潜伏TGFbeta2洗脱峰对应的三个主要的TGFbeta2活性峰。虽然已知前列腺细胞可以激活潜伏的tgf - β，但其激活机制目前尚不清楚。我们研究了前列腺特异性抗原（PSA），一种用作前列腺癌临床标志物的丝氨酸蛋白酶，是否在激活潜伏的tgf - β中发挥作用。与已知的潜伏TGFbeta1和2的激活剂纤溶酶不同，PSA特异性地激活了TGFbeta2的重组小潜伏形式，而不是TGFbeta1。因此，前列腺上皮细胞优先产生TGFbeta2异构体，而前列腺产生的一种蛋白酶PSA专门针对TGFbeta异构体的激活。psa介导的潜在TGFbeta2的激活可能是前列腺中自分泌TGFbeta调节的重要机制，并可能有助于骨转移性前列腺癌成骨细胞病变的形成。(C) 2004 Wiley-Liss, Inc。
Three mammalian isoforms of transforming growth factor-beta (TGFbeta) are known, TGFbeta1, 2, and 3, that have non-overlapping functions during development. However, their specific roles in cancers such as prostate cancer are less clear. Here we show that primary cultures of prostatic epithelial cells preferentially produce and activate the latent TGFP2 isoform. Paired cultures of normal and malignant prostate cells from prostate cancer patients produced predominantly the TGFP2 isoform, with 30- to 70-fold less TGFbeta1. By mono-Q ion exchange chromatography, three major peaks of latent TGFbeta2 activity were observed corresponding to the known small latent TGFbeta2 complex, the known large latent TGFbeta2 complex and a novel eluting peak of latent TGFbeta2. Although prostate cells are known to activate latent TGFbeta, the mechanism for activation is currently unclear. We investigated whether prostate specific antigen (PSA), a serine protease used as a clinical marker for prostate cancer, could play a role in the activation of latent TGFbeta. Unlike plasmin, a known activator of both latent TGFbeta1 and 2, PSA specifically activated the recombinant small latent form of TGFbeta2, but not TGFbeta1. Prostate epithelial cells, therefore, preferentially produce the TGFbeta2 isoform and PSA, a protease produced by the prostate, specifically targets the activation of this TGFbeta isoform. PSA-mediated activation of latent TGFbeta2 may be an important mechanism for autocrine TGFbeta regulation in the prostate and may potentially contribute to the formation of osteoblastic lesions in bone metastatic prostate cancer. (C) 2004 Wiley-Liss, Inc.