Dipeptidyl peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway
Dipeptidyl peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway
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DOI：
10.1158/0008-5472.can-04-1852
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发表时间：
2005-02-15
期刊：
影响因子：
11.2
通讯作者：
Homoyouni, A
中科院分区：
文献类型：
--
作者：
Wesley, UV;McGroarty, A;Homoyouni, A
二肽基肽酶IV（DPPIV）是一种丝氨酸蛋白酶，具有肿瘤抑制功能。它调节在癌症发展中暗示的促有丝分裂肽的活性。良性前列腺癌向恶性转移的进展与碱性成纤维细胞生长因子（bFGF）的产生增加有关，碱性成纤维细胞生长因子是一种强大的促分裂原。在这项研究中，使用体外模型系统，我们表明，DPPIV损失与转移性前列腺癌细胞中bFGF的产生增加有关。DPPIV在前列腺癌细胞中的再表达阻断bFGF的核定位，降低bFGF水平，抑制丝裂原活化蛋白激酶（MAPK）-细胞外信号调节激酶（ERK）1/2活化，并降低尿激酶型纤溶酶原激活物（bFGF信号传导途径的已知下游效应物）的水平。这些分子变化伴随着诱导凋亡、细胞周期阻滞、体外细胞迁移和侵袭的抑制。通过小干扰RNA沉默DPPIV导致bFGF水平增加和丝裂原活化蛋白激酶（MAPK）-细胞外信号调节激酶（ERK）1/2激活的恢复。这些结果表明DPPIV通过阻断bFGF信号通路抑制前列腺癌细胞的恶性表型。
DiPeptidyl peptidase IV (DPPIV) is a serine protease with tumor suppressor function. It regulates the activities of mitogenic peptides implied in cancer development. Progression of benign prostate cancer to malignant metastasis is linked to increased production of basic fibroblast growth factor (bFGF), a powerful mitogen. In this study, using in vitro model system we show that DPPIV loss is associated with increased bFGF production in metastatic prostate cancer cells. DPPIV reexpression in prostate cancer cells blocks nuclear localization of bFGF, reduces bFGF levels, inhibits mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)1/2 activation, and decreases levels of urokinase-type plasminogen activator, known downstream effectors of bFGF signaling pathway. These molecular changes were accompanied by induction of apoptosis, cell cycle arrest, inhibition of in vitro cell migration, and invasion. Silencing of DPPIV by small interfering RNA resulted in increased bFGF levels and restoration of mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)1/2 activation. These results indicate that DPPIV inhibits the malignant phenotype of prostate cancer cells by blocking bFGF signaling pathway.