The metalloproteinase inhibitor TIMP-2 is down-regulated by androgens in LNCaP prostate carcinoma cells
The metalloproteinase inhibitor TIMP-2 is down-regulated by androgens in LNCaP prostate carcinoma cells
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DOI：
10.1023/a:1025860214891
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发表时间：
2003-01-01
影响因子：
4
通讯作者：
Ree, AH
中科院分区：
文献类型：
--
作者：
Bratland, Å;Ragnhildstveit, E;Ree, AH
金属蛋白酶组织抑制剂（TIMP）已被证明在肿瘤促进中发挥多种生物学功能，主要是通过它们在转移过程的不同步骤抑制基质金属蛋白酶（MMP）的作用。特别是，TIMP-2 参与与膜型 1 (MT1) MMP 的功能复合物，将分泌的 MMP-2 原明胶酶转化为完全活性的蛋白水解酶。我们使用人类雄激素敏感的前列腺癌细胞系 LNCaP 与人类骨肉瘤细胞系 OHS 共培养，通过实验探讨在前列腺癌骨转移过程中，前列腺癌与成骨细胞相互作用时，雄激素依赖性调节作用对功能性 MT1-MMP/TIMP-2/MMP-2 复合物的可能性。在 LNCaP 细胞中，在合成雄激素类似物 R1881 (100 nM) 存在的情况下，观察到 TIMP-2 mRNA 表达逐渐、时间依赖性下降，孵育 48 小时后达到与对照水平相似的 25%。与此一致，3小时后，R1881处理的细胞的培养基中分泌的TIMP-2的积累已被显着抑制。在 LNCaP 细胞中未检测到 MMP-2 明胶分解活性和 MT1-MMP 表达。相反，OHS 细胞表现出膜相关的 MT1-MMP 表达以及 MMP-2 分泌。然而，LNCaP/OHS 共培养模型的 R1881 处理似乎没有改变 MT1-MMP/TIMP-2/MMP-2 复合物的整体蛋白水解活性。此前尚未报道前列腺癌细胞中TIMP-2表达的激素控制，但这种调节在前列腺癌成骨细胞转移的发展中是否具有任何功能作用仍不清楚。
Tissue inhibitors of metalloproteinases (TIMPs) have been shown to perform several biological functions in tumor promotion, principally by their action of inhibiting matrix metalloproteinases (MMPs) at different steps of the metastatic process. In particular, TIMP-2 is involved in a functional complex with the membrane-type 1 (MT1) MMP to convert the secreted MMP-2 progelatinase into the fully active proteolytic enzyme. We used the human, androgen-sensitive prostate carcinoma cell line LNCaP in coculture with the human osteosarcoma cell line OHS to experimentally address the possibility of androgen-dependent regulatory effects on the functional MT1-MMP/TIMP-2/MMP-2 complex upon interaction between prostate carcinoma and osteoblastic cells in metastasis of prostate cancer to bone. In the LNCaP cells a gradual, time-dependent decline in TIMP-2 mRNA expression was observed in the presence of the synthetic androgen analogue R1881 (100 nM), reaching similar to25% of the control level after 48 h of incubation. Consistent with this, the accumulation of secreted TIMP-2 in media from R1881-treated cells was significantly inhibited already after 3 h. Neither MMP-2 gelatinolytic activity nor expression of MT1-MMP was detected in LNCaP cells. In contrast, the OHS cells showed membrane-associated MT1-MMP expression as well as MMP-2 secretion. However, R1881 treatment of the LNCaP/OHS coculture model did not seem to change the overall proteolytic activity of the MT1-MMP/TIMP-2/MMP-2 complex. Hormonal control of TIMP-2 expression in prostate carcinoma cells has not been previously reported, but whether such regulation has any functional role in the development of osteoblastic metastases in prostate cancer is still unclear.