Inhibition of HIF-1 alpha and VEGF expression by the chemopreventive bioflavonoid apigenin is accompanied by akt inhibition in human prostate carcinoma PC3-M cells
Inhibition of HIF-1 alpha and VEGF expression by the chemopreventive bioflavonoid apigenin is accompanied by akt inhibition in human prostate carcinoma PC3-M cells
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DOI：
10.1002/mc.20421
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发表时间：
2008-09-01
影响因子：
4.6
通讯作者：
Pelling, Jill C.
中科院分区：
文献类型：
--
作者：
Mirzoeva, Salida;Kim, Nam Deuk;Pelling, Jill C.
癌症的进展导致低氧实体瘤，其对低氧条件产生特异性细胞信号传导反应。抗癌治疗的一个重要目标是开发抑制实体瘤中缺氧反应的新药。芹菜素是一种天然黄酮，已被证明对许多肿瘤类型具有化学预防和/或抗癌特性。然而，芹菜素的化学预防特性的机制尚未完全了解。在本研究中，我们研究了芹菜素对人转移性前列腺癌PC 3-M细胞中缺氧诱导因子-1（HIF-1）表达的影响。我们发现，缺氧诱导PC 3-M细胞中HIF-1 α亚基蛋白水平的时间依赖性增加，并且在常氧和缺氧条件下用芹菜素处理显著降低HIF-1 α表达。此外，芹菜素阻止HIF-1下游靶基因血管内皮生长因子（VEGF）的激活。然后，我们发现芹菜素通过降低蛋白质的稳定性以及通过降低HIF-1 α mRNA的水平来抑制HIF-1 α的表达。我们还发现芹菜素抑制PC 3-M细胞中Akt和GSK-3 β的磷酸化。进一步的实验表明，组成型激活的Akt减弱了芹菜素对HIF-1 α表达的影响。综上所述，我们的研究结果将芹菜素鉴定为抑制与人类前列腺癌中的癌症进展相关的缺氧激活途径的生物素，特别是PI 3 K/Akt/GSK-3途径。对芹菜素作用机制的进一步研究将可能为其用于癌症治疗或化学预防目的的HIF-1 α药理学靶向的适用性提供新的见解。(C)2008 Wiley-Liss Inc.
Progression of cancer leads to hypoxic solid tumors that mount specific cell signaling responses to low oxygen conditions. An important objective of anti-cancer therapy is the development of new drugs that suppress hypoxic responses in solid tumors. Apigenin is a natural flavone that has been shown to have chemopreventive and/or anticancer properties against a number of tumor types. However, the mechanisms underlying apigenin's chemopreventive properties are not yet completely understood. in this study, we have investigated the effects of apigenin on expression of hypoxia-inducible factor-1 (HIF-1) in human metastatic prostate PC3-M cancer cells. We found that hypoxia induced a time-dependent increase in the level of HIF-1 alpha subunit protein in PC3-M cells, and treatment with apigenin markedly decreased HIF-1 alpha expression under both normoxic and hypoxic conditions. Further, apigenin prevented the activation of the HIF-1 downstream target gene vascular endothelial growth factor (VEGF). We then showed that apigenin inhibited expression of HIF-1 alpha by reducing stability of the protein as well as by reducing the level of HIF-1 a mRNA. We also found that apigenin inhibited Akt and GSK-3 beta phosphorylation in PC3-M cells. Further experiments demonstrated that constitutively active Akt blunted the effect of apigenin on HIF-1 a expression. Taken together, our results identify apigenin as a bioflavonoid that inhibits hypoxia-activated pathways linked to cancer progression in human prostate cancer, in particular the PI3K/Akt/GSK-3 pathway. Further studies on the mechanism of action of apigenin will likely provide new insight into its applicability for pharmacologic targeting of HIF-1 alpha for cancer therapeutic or chemopreventive purposes. (C) 2008 Wiley-Liss Inc.