McKenzie S, Sakamoto S, Kyprianou N
Division of Urology, Department of Surgery, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
Oncogene. 2008 Dec 4;27(57):7171-9. doi: 10.1038/onc.2008.321. Epub 2008 Oct 20.
Hypoxia has been previously linked to the development of both benign prostatic hyperplasia and prostate cancer. This study investigated the effect of maspin, an extracellular matrix (ECM) tumor suppressor, on the apoptotic response of prostate cancer cells to hypoxia. Gene expression profiling of human benign and malignant prostate epithelial cells after exposure to hypoxia or normoxia revealed dramatic changes in ECM regulators. Maspin was found to be overexpressed in response to hypoxia in prostate cancer cells, but not in benign prostate cells. To dissect the contribution of maspin to tumor cell responses within a hypoxic microenvironment, we used maspin-overexpressing DU-145 human prostate cancer cells. Exposure to hypoxic conditions (1% O(2)) led to a significant increase in apoptosis in the DU-145 maspin cells, compared to DU-145 neo-transfectants without a significant effect on cell migration. This enhanced sensitivity to hypoxia-induced apoptosis leads to a significant suppression of tumor growth and tumor vascularity in vivo by targeting Akt and focal adhesion kinase activation. Our findings implicate maspin in prostate cancer cell response to hypoxia via recruitment of intracellular signaling partners. This study may have significance in the identification of maspin-driven therapeutic targeting in advanced metastatic prostate cancer.
低氧血症此前已被证明与良性前列腺增生和前列腺癌的发展有关。本研究调查了细胞外基质（ECM）肿瘤抑制因子maspin对前列腺癌细胞低氧凋亡反应的影响。对暴露于低氧或常氧环境下的人良性和恶性前列腺上皮细胞进行基因表达谱分析，结果显示ECM调节因子发生了显著变化。研究发现，maspin在前列腺癌细胞中对低氧有过表达反应，但在良性前列腺细胞中则不然。为了剖析maspin在低氧微环境中对肿瘤细胞反应的作用，我们使用了过表达maspin的DU-145人前列腺癌细胞。与未转染的DU-145细胞相比，暴露于低氧条件（1% O₂）下的DU-145 maspin细胞凋亡显著增加，且对细胞迁移无显著影响。这种对低氧诱导凋亡的敏感性增强通过靶向Akt和粘着斑激酶激活，导致体内肿瘤生长和肿瘤血管生成受到显著抑制。我们的研究结果表明，maspin通过招募细胞内信号伙伴参与前列腺癌细胞对低氧的反应。本研究对于确定maspin驱动的晚期转移性前列腺癌治疗靶点可能具有重要意义。
