Matriptase activation and shedding with HAI-1 is induced by steroid sex hormones in human prostate cancer cells, but not in breast cancer cells
Matriptase activation and shedding with HAI-1 is induced by steroid sex hormones in human prostate cancer cells, but not in breast cancer cells
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DOI：
10.1152/ajpcell.00351.2005
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发表时间：
2006-07-01
影响因子：
5.5
通讯作者：
Lin, Chen-Yong
中科院分区：
文献类型：
--
作者：
Kiyomiya, Ken-ichi;Lee, Ming-Shyue;Lin, Chen-Yong
Mattritase及其同源抑制物肝细胞生长因子激活物抑制物-1(HAI-1)与肿瘤的发生和恶性进展密切相关。然而，Mattritase激活的病理机制尚不清楚。类固醇性激素在前列腺癌和乳腺癌中起着关键作用。因此，我们调查了类固醇性激素是否以及如何调节这些癌细胞中的Mattritase激活的问题。用17β-雌二醇处理细胞对激素缺乏的乳腺癌细胞中的Mattritase的激活没有影响，部分原因是它们的高组成水平的激活的Mattritase。与之形成鲜明对比的是，在激素匮乏的淋巴前列腺癌(LNCaP)细胞中检测到极低水平的激活的Mattritase。在这些细胞暴露于5α-双氢睾酮(DHT)后6h，就观察到Mattritase的强烈激活。DHT处理24小时后，底物中90%的活性底物脱除，紧随其后的是底物中活化的底物。活化的麦曲霉酶在与HAI-1的复合体中脱落，可能是两种膜结合蛋白同时被蛋白水解酶切割的结果。同时，将潜伏期的基质酶和游离的HAI-1分别加入到培养基中。DHT作用24 h后，细胞中的Mattritase和HAI-1水平显著降低。雄激素拮抗剂比卡鲁胺、RNA转录抑制剂放线菌素D和蛋白质合成抑制剂放线菌胺均显著抑制DHT诱导的Mattritase的激活和脱落。这些结果表明，在LNCaP细胞中，雄激素通过雄激素受体诱导Mattritase激活，并需要转录和蛋白质合成。
Matriptase and its cognate inhibitor, hepatocyte growth factor activator inhibitor-1 (HAI-1), have been implicated in carcinoma onset and malignant progression. However, the pathological mechanisms of matriptase activation are not defined. Steroid sex hormones play crucial roles in prostate and breast cancer. Therefore, we investigated the questions of whether and how steroid sex hormones regulate matriptase activation in these cancer cells. Treatment of cells with 17 beta-estradiol had no effect on activation of matriptase in hormone-starved breast cancer cells, in part due to their high constitutive level of activated matriptase. In striking contrast, very low levels of activated matriptase were detected in hormone- starved lymph node prostatic adenocarcinoma (LNCaP) cells. Robust activation of matriptase was observed as early as 6 h after exposure of these cells to 5 alpha-dihydrotestosterone (DHT). Activation of matriptase was closely followed by shedding of the activated matriptase with > 90% of total activated matriptase present in the culture media 24 h after DHT treatment. Activated matriptase was shed in a complex with HAI-1 and may result from simultaneously proteolytic cleavages of both membrane-bound proteins. Latent matriptase and free HAI-1 were also shed into culture media. As a result of shedding, the cellular levels of matriptase and HAI-1 were significantly reduced 24 h after exposure to DHT. DHT-induced matriptase activation and shedding were significantly inhibited by the androgen antagonist bicalutamide, by the RNA transcription inhibitor actinomycin D, and by the protein synthesis inhibitor cycloheximide. These results suggest that in LNCaP cells, androgen induces matriptase activation via the androgen receptor, and requires transcription and protein synthesis.