Peroxiredoxin 1 controls prostate cancer growth through Toll-like receptor 4-dependent regulation of tumor vasculature.
Peroxiredoxin 1 controls prostate cancer growth through Toll-like receptor 4-dependent regulation of tumor vasculature.
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DOI：
10.1158/0008-5472.can-10-3674
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发表时间：
2011-03-01
期刊：
影响因子：
11.2
通讯作者：
Gollnick SO
中科院分区：
文献类型：
--
作者：
Riddell JR;Bshara W;Moser MT;Spernyak JA;Foster BA;Gollnick SO
近年来，许多研究表明慢性炎症与前列腺癌的发生有关。然而，前列腺炎症的缓解因素几乎是未知的。Toll样受体4（TLR4）活性与炎症相关，并与前列腺癌（CaP）的进展风险相关。TLR4配体包括细菌细胞壁蛋白、危险信号蛋白和细胞内蛋白如热休克蛋白和过氧化物氧还蛋白1（Prx1）。在这里，我们表明，Prx1在人类CaP标本中过表达，它通过TLR4依赖性调节前列腺肿瘤血管系统来调节前列腺肿瘤的生长。抑制前列腺肿瘤细胞中Prx1的表达减少了肿瘤血管的形成和功能。此外，Prx1抑制降低了肿瘤微环境中血管生成蛋白如VEGF的水平。最后，Prx 1以TLR 4和VEGF依赖的方式刺激内皮细胞增殖、迁移和分化。总之，这些结果暗示Prx1作为肿瘤衍生的炎症诱导剂，在前列腺癌发生中提供炎症和TLR4之间的机制联系。我们的研究结果暗示Prx1作为CaP的新治疗靶点。
In recent years a number of studies have implicated chronic inflammation in prostate carcinogenesis. However, mitigating factors of inflammation in the prostate are virtually unknown. Toll-like receptor 4 (TLR4) activity is associated with inflammation and is correlated with progression risk in prostate cancer (CaP). TLR4 ligands include bacterial cell wall proteins, danger signaling proteins, and intracellular proteins such as heat shock proteins and peroxiredoxin 1 (Prx1). Here we show that Prx1 is overexpressed in human CaP specimens and that it regulates prostate tumor growth through TLR4-dependent regulation of prostate tumor vasculature. Inhibiting Prx1 expression in prostate tumor cells reduced tumor vascular formation and function. Further, Prx1 inhibition reduced levels of angiogenic proteins such as VEGF within the tumor microenvironment. Lastly, Prx1 stimulated endothelial cell proliferation, migration and differentiation in a TLR4- and VEGF-dependent manner. Taken together, these results implicate Prx1 as a tumor-derived inducer of inflammation, providing a mechanistic link between inflammation and TLR4 in prostate carcinogenesis. Our findings implicate Prx1 as a novel therapeutic target for CaP.