Alaoui-Jamali Moulay A, Bismar Tarek A, Gupta Ajay, Szarek Walter A, Su Jie, Song Wei, Xu Yingjie, Xu Bin, Liu Guoan, Vlahakis Jason Z, Roman Gheorghe, Jiao Jinsong, Schipper Hyman M
Department of Medicine, Lady Davis Institute of Medical Research, Segal Cancer Centre, McGill University, Montreal, Quebec, Canada.
Cancer Res. 2009 Oct 15;69(20):8017-24. doi: 10.1158/0008-5472.CAN-09-0419. Epub 2009 Oct 6.
Heme oxygenase-1 (HO-1), a member of the heat shock protein family, plays a key role as a sensor and regulator of oxidative stress. Herein, we identify HO-1 as a biomarker and potential therapeutic target for advanced prostate cancer (PCA). Immunohistochemical analysis of prostate tissue using a progression tissue microarray from patients with localized PCA and across several stages of disease progression revealed a significant elevation of HO-1 expression in cancer epithelial cells, but not in surrounding stromal cells, from hormone-refractory PCA (HRPCA) compared with hormone-responsive PCA and benign tissue. Silencing the ho-1 gene in HRPCA cells decreased the HO-1 activity, oxidative stress, and activation of the mitogen-activated protein kinase-extracellular signal-regulated kinase/p38 kinase. This coincided with reduced cell proliferation, cell survival, and cell invasion in vitro, as well as inhibition of prostate tumor growth and lymph node and lung metastases in vivo. The effect of ho-1 silencing on these oncogenic features was mimicked by exposure of cells to a novel selective small-molecule HO-1 inhibitor referred to as OB-24. OB-24 selectively inhibited HO-1 activity in PCA cells, which correlated with a reduction of protein carbonylation and reactive oxygen species formation. Moreover, OB-24 significantly inhibited cell proliferation in vitro and tumor growth and lymph node/lung metastases in vivo. A potent synergistic activity was observed when OB-24 was combined with Taxol. Together, these results establish HO-1 as a potential therapeutic target for advanced PCA.
血红素加氧酶-1（HO-1）是热休克蛋白家族的一员，作为氧化应激的传感器和调节因子发挥关键作用。在此，我们确定HO-1是晚期前列腺癌（PCA）的生物标志物和潜在治疗靶点。使用来自局限性PCA患者的进展组织微阵列并跨越疾病进展的几个阶段对前列腺组织进行免疫组织化学分析显示，与激素反应性PCA和良性组织相比，激素难治性PCA（HRPCA）的癌上皮细胞中HO-1表达显著升高，而周围基质细胞中则未升高。沉默HRPCA细胞中的ho-1基因可降低HO-1活性、氧化应激以及丝裂原活化蛋白激酶-细胞外信号调节激酶/p38激酶的激活。这与体外细胞增殖、细胞存活和细胞侵袭的减少以及体内前列腺肿瘤生长和淋巴结及肺转移的抑制相吻合。细胞暴露于一种新型选择性小分子HO-1抑制剂OB-24可模拟ho-1沉默对这些致癌特征的影响。OB-24选择性抑制PCA细胞中的HO-1活性，这与蛋白质羰基化和活性氧形成的减少相关。此外，OB-24在体外显著抑制细胞增殖，在体内抑制肿瘤生长和淋巴结/肺转移。当OB-24与紫杉醇联合使用时观察到强效协同活性。总之，这些结果确立了HO-1作为晚期PCA潜在治疗靶点的地位。
