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首页> 外文期刊>Cell biology international. >Administration of IB-kinase inhibitor PS1145 enhances apoptosis in DMBA-induced tumor in male Wistar rats
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Administration of IB-kinase inhibitor PS1145 enhances apoptosis in DMBA-induced tumor in male Wistar rats

机译：给予IB激酶抑制剂PS1145可增强DMBA诱导的雄性Wistar大鼠肿瘤的凋亡

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摘要

Nuclear factor kappa-B (NF-B), a key anti-apoptotic factor, plays a critical role in tumor cell growth, metastasis, and angiogenesis. The transcriptional activity of NF-B is normally suppressed in the cytoplasm due to its association with a natural inhibitor molecule IB. Phosphorylation of the IB at Ser 32 and Ser 36 by the IB kinase complex (IKK) marks the degradation of the molecule by 26S proteasome. As NF-B is constitutively activated in most of the tumor cells, inhibition of the activities of IKK may significantly sensitize the tumor cells to apoptosis. In the present study, we investigated the effect of IB kinase-specific blocker PS1145 on DMBA-induced skin tumor of male Wistar rats. We examined the apoptotic effect of PS1145 on DMBA-induced tumor by various histopathological and molecular techniques. Our results demonstrate the significant expression of major pro-apoptotic genes like caspases 2, 3, 8, 9, and p53 in PS1145-treated tumor bearing group at mRNA levels as well as significant (P<0.05) down regulation in the expression levels of NF-B and VEGF, the major pro-inflammatory and pro-angiogenic factors, respectively. The histopathological examination showed that the tumor progression, mitotic, AgNOR, and PCNA indices were significantly reduced in PS1145 treatment groups as compared to PBS control on day 28 of post-treatment. Furthermore, significant increase in TUNEL positive nuclei and observation of peculiar apoptotic nuclei in transmission electron microscopy were seen in PS1145 treatment group. We conclude that intravenous application of PS1145 promotes direct apoptosis in DMBA-induced skin tumor in male Wistar rats by blocking NF-B and VEGF activities.
机译：核因子κB（NF-B）是关键的抗凋亡因子，在肿瘤细胞的生长，转移和血管生成中起着至关重要的作用。由于NF-B与天然抑制剂分子IB缔合，因此通常在细胞质中抑制NF-B的转录活性。 IB激酶复合物（IKK）对Ser 32和Ser 36处IB的磷酸化标志着该分子被26S蛋白酶体降解。由于NF-B在大多数肿瘤细胞中被组成性激活，因此抑制IKK的活性可能会使肿瘤细胞对凋亡产生明显的敏感性。在本研究中，我们研究了IB激酶特异性阻滞剂PS1145对DMBA诱导的雄性Wistar大鼠皮肤肿瘤的影响。我们通过各种组织病理学和分子技术检查了PS1145对DMBA诱导的肿瘤的凋亡作用。我们的结果证明PS1145治疗的荷瘤组中主要促凋亡基因（例如胱天蛋白酶2、3、8、9和p53）在mRNA水平上显着表达，并且在（p <0.05）显着下调表达水平。 NF-B和VEGF分别是主要的促炎和促血管生成因子。组织病理学检查显示与治疗后第28天的PBS对照相比，PS1145治疗组的肿瘤进展，有丝分裂，AgNOR和PCNA指数显着降低。此外，在PS1145治疗组中观察到TUNEL阳性细胞核显着增加，并且在透射电镜中观察到特异的凋亡细胞核。我们得出的结论是，静脉注射PS1145可通过阻断NF-B和VEGF活性促进DMBA诱导的雄性Wistar大鼠皮肤肿瘤中的直接凋亡。

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