Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype
Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype
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DOI：
10.1158/0008-5472.can-07-5259
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发表时间：
2008-03-15
期刊：
影响因子：
11.2
通讯作者：
Koul, Hari K.
中科院分区：
文献类型：
--
作者：
Kumar, Binod;Koul, Sweaty;Koul, Hari K.
活性氧（ROS）和氧化应激与肿瘤的形成有关。一些研究表明，活性氧可以作为第二信使和控制各种信号级联反应。在目前的研究中，我们的特点在三个不同的前列腺癌细胞（PC 3，DU 145，和LNCaP）表现出不同程度的侵略性和正常前列腺细胞培养（WPMY 1，RWPE 1，和正常上皮细胞的原代培养物）的氧化应激状态。我们观察到与正常细胞相比，癌细胞中ROS产生增加，并且ROS产生器的线粒体外来源NAD（P）H氧化酶（Nox）系统与ROS产生相关，并且对于前列腺癌细胞的恶性表型至关重要。Nox特异性抑制剂二苯基碘鎓（diphenyliodonium，diphenylidonium）可抑制细胞增殖，调节细胞外信号调节激酶（extracellular signal-regulated kinase，ERK）1/ERK 2和p38丝裂原活化蛋白激酶（mitogen-activated protein kinase，p38）以及AKT蛋白激酶B（proteinkinaseB，AKT）的活性，导致细胞周期蛋白B依赖性的G（2）-M期阻滞。我们还观察到PC 3细胞中ROS产生的程度高于DU 145和LNCaP，并且ROS产生对于迁移/侵袭表型至关重要。此外，阻断ROS产生而不是ROS中和导致基质金属蛋白酶9活性降低以及线粒体电位丧失，这是细胞侵袭减少和细胞死亡增加的合理原因。总之，这些研究首次显示了线粒体外来源的ROS产生在前列腺癌中的重要作用，并表明旨在减少ROS产生的疗法可能特别提供对抗前列腺癌的有效手段，并且可能是一般的其他恶性肿瘤。
Reactive oxygen species (ROS) and the coupled oxidative stress have been associated with tumor formation. Several studies suggested that ROS can act as secondary messengers and control various signaling cascades. In the present studies, we characterized the oxidative stress status in three different prostate cancer cells (PC3, DU145, and LNCaP) exhibiting various degree of aggressiveness and normal prostate cells in culture (WPMY1, RWPE1, and primary cultures of normal epithelial cells). We observed increased ROS generation in cancer cells compared with normal cells, and that extramitochondrial source of ROS generator, NAD(P)H oxidase (Nox) systems, are associated with the ROS generation and are critical for the malignant phenotype of prostate cancer cells. Moreover, diphenyliodonium, a specific Nox inhibitor, blocked proliferation, modulated the activity of growth signaling cascades extracellular signal-regulated kinase (ERK)1/ERK2 and p38 mitogen-activated protein kinase as well as AKT protein kinaseB, and caused cyclin B-dependent G(2)-M cell cycle arrest. We also observed higher degrees of ROS generation in the PC3 cells than DU145 and LNCaP, and that ROS generation is critical for migratory/invasiveness phenotypes. Furthermore, blocking of the ROS production rather than ROS neutralization resulted in decreased matrix metalloproteinase 9 activity as well as loss of mitochondrial potential, plausible reasons for decreased cell invasion and increased cell death. Taken together, these studies show, for the first time, the essential role of ROS production by extramitochondrial source in prostate cancer and suggest that therapies aimed at reducing ROS production might offer effective means of combating prostate cancer in particular, and perhaps other malignancies in general.