Intracellular hydrogen peroxide production is an upstream event in apoptosis induced by down-regulation of casein kinase 2 in prostate cancer cells
Intracellular hydrogen peroxide production is an upstream event in apoptosis induced by down-regulation of casein kinase 2 in prostate cancer cells
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DOI：
10.1158/1541-7786.mcr-06-0073
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发表时间：
2006-05-01
影响因子：
5.2
通讯作者：
Ahmed, Khalil
中科院分区：
文献类型：
--
作者：
Ahmad, Kashif A.;Wang, Guixia;Ahmed, Khalil
我们以前已经证明，通过使用其抑制剂芹菜素或4，5，6，7-四溴苯并三唑下调CK2的活性(蛋白激酶CK2，以前的酪蛋白激酶2)，可以促进前列腺癌细胞的凋亡。为了确定这一作用的下游介质，我们发现在各种正常细胞和癌细胞中，CK2下调所观察到的细胞凋亡之前是细胞内产生氢氧化物(H_2O_2)。在这一点上，雄激素依赖型ALVA-41细胞和雄激素非依赖性PC-3细胞经80mU/L芹菜素、4，5，6，7-四溴苯并三氮唑、反义CK2α寡核苷酸或小干扰RNA处理后，对CK2下调的反应类似。有趣的是，尽管CK2的化学抑制剂在癌细胞和非癌细胞中都能诱导过氧化氢的产生，但反义CK2α介导的CK2的下调在癌细胞中显示出显著的过氧化氢产生，但对非癌细胞的影响很小。这一关键差异的基础目前尚不清楚，但这一观察结果可能对反义CK2寡核苷酸在癌症治疗中的治疗潜力有影响。反义CK2α诱导的过氧化氢的产生与前列腺癌细胞(Alva-41和PC-3)中caspase-3的活性、核因子-kappa B的核转位、细胞色素c的释放以及随后的DNA断裂有关。这些发现首次描述了CK2与活性氧之间的关系，即抑制CK2导致细胞内过氧化氢的产生，而过氧化氢可能是癌细胞凋亡的下游中介。
We have shown previously that down-regulation of CK2 activity (protein kinase CK2, formerly casein kinase 2) by employing its inhibitors apigenin or 4,5,6, 7-tetrabromobenzotriazole promotes apoptosis in prostatic carcinoma cells. In an effort to define the downstream mediators of this action, we show that cell apoptosis observed on down-regulation of CK2 is preceded by intracellular generation of hydrogen hydroxide (H2O2) in various normal and cancer cells. In this regard, both androgen-dependent ALVA-41 and androgen-independent PC-3 cells treated with 80 mu mol/L apigenin or 4,5,6,7-tetrabromobenzotriazole or with antisense CK2 alpha oligonucleotide or small interfering RNA respond similarly to down-regulation of CK2. Interestingly, whereas chemical inhibitors of CK2 elicited H2O2 production in both cancer and noncancer cells, the antisense CK2 alpha-mediated down-regulation of CK2 showed significant H2O2 production in cancer cells but had minimal effect in noncancer cells. The basis of this key difference is unclear at present, but this observation may have implications for the therapeutic potential of antisense CK2 oligonucleotide in cancer therapy. The H2O2 production induced by antisense CK2 alpha was associated with robust caspase-3 activity, nuclear factor-kappa B nuclear translocation, cytochrome c release, and subsequent DNA fragmentation in prostate cancer cells (ALVA-41 and PC-3). These findings describe, for the first time, a relationship between CK2 and reactive oxygen species, such that CK2 inhibition leads to production of intracellular H2O2, which may serve as a downstream mediator of apoptosis in cancer cells.