Apigenin induces apoptosis via downregulation of S-phase kinase-associated protein 2-mediated induction of p27Kip1 in primary effusion lymphoma cells
Apigenin induces apoptosis via downregulation of S-phase kinase-associated protein 2-mediated induction of p27Kip1 in primary effusion lymphoma cells
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DOI：
10.1111/j.1365-2184.2009.00662.x
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发表时间：
2010-04-01
影响因子：
8.5
通讯作者：
Uddin, S.
中科院分区：
文献类型：
--
作者：
Hussain, A. R.;Khan, A. S.;Uddin, S.
目的：原发性渗出性淋巴瘤（PEL）中促有丝分裂和抗凋亡信号的调节机制尚不清楚。为了寻找阻止 PEL 细胞增殖的新方法，我们评估了芹菜素（4',5,7-三羟基黄酮）（一种黄酮类化合物）对一组 PEL 细胞系的影响。材料和方法：我们研究了芹菜素对四种 PEL 细胞系的影响。通过膜联蛋白 V/PI 双染色和 DNA 梯法测量细胞凋亡。通过免疫印迹法测定蛋白表达。结果：芹菜素以剂量依赖性方式诱导PEL细胞系凋亡。芹菜素的这种作用似乎是由于对组成型活性激酶 AKT 的抑制，导致 SKP2 下调、Rb 低磷酸化和 p27Kip1 积累。 PEL 细胞的芹菜素处理引起 p-Bad 蛋白去磷酸化，从而导致抗凋亡蛋白 Bcl-2 下调和 Bax/Bcl2 比率增加。芹菜素处理还引发 Bax 构象变化，随后从细胞质易位至线粒体，导致线粒体膜电位丧失，随后释放细胞色素 c。将细胞色素 c 释放到胞质激活的 caspase-9 和 caspase-3 上，然后进行聚腺苷酸 5'-二磷酸核糖聚合酶 (PARP) 裂解。最后，用芹菜素处理 PEL 细胞，下调凋亡蛋白抑制剂 (IAP) 的表达。 结论：总而言之，这些数据表明芹菜素具有新功能，可作为 PEL 细胞中 AKT/PKB 通路的抑制剂，并提出该药物未来可能在 PEL 以及其他可能激活 AKT/PKB 通路的恶性肿瘤中发挥治疗作用的可能性。
Objective:The mechanisms that regulate mitogenic and antiapoptotic signals in primary effusion lymphoma (PEL) are not well known. In efforts to identify novel approaches to block the proliferation of PEL cells, we assessed the effect of apigenin (4',5,7-trihydroxyflavone), a flavonoid on a panel of PEL cell lines.Materials and methods:We studied the effect of apigenin on four PEL cell lines. Apoptosis was measured by annexin V/PI dual staining and DNA laddering. Protein expression was measured by immunoblotting.Results:Apigenin induced apoptosis in PEL cell lines in a dose dependent manner. Such effects of apigenin appeared to result from suppression of constitutively active kinase AKT resulting in down-regulation of SKP2, hypo-phosphorylation of Rb and accumulation of p27Kip1. Apigenin treatment of PEL cells caused dephosphorylation of p-Bad protein leading to down regulation of the anti-apoptotic protein, Bcl-2 and an increase in Bax/Bcl2 ratio. Apigenin treatment also triggered Bax conformational change and subsequently translocation from cytosole to mitochondria causing loss of mitochondrial membrane potential with subsequent release of cytochrome c. Released cytochrome c onto the cytosole activated caspase-9 and caspase-3, followed by polyadenosin-5'-diphosphate-ribose polymerase (PARP) cleavage. Finally, treatment of PEL cells with apigenin down-regulated the expression of inhibitor of apoptosis protein (IAPs).Conclusions:Altogether, these data suggest a novel function for apigenin, acting as a suppressor of AKT/PKB pathway in PEL cells, and raise the possibility that this agent may have a future therapeutic role in PEL and possibly other malignancies with constitutive activation of the AKT/PKB pathway.