| MFTZ-1 reduces constitutive and inducible HIF-1 alpha accumulation and VEGF secretion independent of its topoisomerase II inhibition | |
| Dai, Mei1; Miao, Ze-Hong1; Ren, Xuan1; Tong, Lin-Jiang1; Yang, Na1; Li, Ting1; Lin, Li-Ping1; Shen, Yue-Mao2; Ding, Jian1 | |
| 2010-09-01 | |
| 发表期刊 | JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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| 卷号 | 14期号:9页码:2281-2291 |
| 摘要 | The macrolide compound MFTZ-1 has been identified as a novel topoisomerase II (Top2) inhibitor with potent in vitro and in vivo anti-tumour activities. In this study, we further examined the effects of MFTZ-1 on hypoxia-inducible factor-1 alpha (HIF-1 alpha) accumulation, vascular endothelial growth factor (VEGF) secretion and angiogenesis. MFTZ-1 reduced HIF-1 alpha accumulation driven by hypoxia or growth factors in human cancer cells. Mechanistic studies revealed that MFTZ-1 did not affect the degradation of HIF-1 alpha protein or the level of HIF-1 alpha mRNA. By contrast, MFTZ-1 apparently inhibited constitutive and inducible activation of both phosphatidylinositol-3-kinase (PI3K)-Akt and p42/p44 mitogen-activated protein kinase (MAPK) pathways. Further studies revealed that MFTZ-1 abrogated the HIF-1 alpha-driven increase in VEGF mRNA and protein secretion. MFTZ-1 also lowered the basal level of VEGF secretion. The results reveal an important feature that MFTZ-1 can reduce constitutive, HIF-1 alpha-independent VEGF secretion and concurrently antagonize inducible, HIF-1 alpha-dependent VEGF secretion. Moreover, MFTZ-1 disrupted tube formation of human umbilical vein endothelial cells (HUVECs) stimulated by hypoxia with low-concentration serum or by serum at normoxia, and inhibited HUVECs migration at normoxia. MFTZ-1 also prevented microvessel outgrowth from rat aortic ring. These data reflect the potent anti-angiogenesis of MFTZ-1 under different conditions. Furthermore, using specific small interfering RNA targeting Top2 alpha or Top2-defective HL60/MX2 cells, we showed that MFTZ-1 affected HIF-1 alpha accumulation and HUVECs tube formation irrelevant to its Top2 inhibition. Taken together, our data collectively reveal that MFTZ-1 reduces constitutive and inducible HIF-1 alpha accumulation and VEGF secretion possibly via PI3K-Akt and MAPK pathways, eliciting anti-angiogenesis independently of its Top2 inhibition. |
| 关键词 | Mftz-1 Hif-1 Alpha Vegf Angiogenesis Topoisomerase Ii Inhibitor |
| DOI | 10.1111/j.1582-4934.2009.00822.x |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS记录号 | WOS:000282874000014 |
| 引用统计 | |
| 文献类型 | 期刊论文 |
| 条目标识符 | http://ir.kib.ac.cn/handle/151853/23915 |
| 专题 | 植物化学与西部植物资源持续利用国家重点实验室 |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resouces W China, Kunming, Peoples R China |
| 推荐引用方式 GB/T 7714 | Dai, Mei,Miao, Ze-Hong,Ren, Xuan,et al. MFTZ-1 reduces constitutive and inducible HIF-1 alpha accumulation and VEGF secretion independent of its topoisomerase II inhibition[J]. JOURNAL OF CELLULAR AND MOLECULAR MEDICINE,2010,14(9):2281-2291. |
| APA | Dai, Mei.,Miao, Ze-Hong.,Ren, Xuan.,Tong, Lin-Jiang.,Yang, Na.,...&Ding, Jian.(2010).MFTZ-1 reduces constitutive and inducible HIF-1 alpha accumulation and VEGF secretion independent of its topoisomerase II inhibition.JOURNAL OF CELLULAR AND MOLECULAR MEDICINE,14(9),2281-2291. |
| MLA | Dai, Mei,et al."MFTZ-1 reduces constitutive and inducible HIF-1 alpha accumulation and VEGF secretion independent of its topoisomerase II inhibition".JOURNAL OF CELLULAR AND MOLECULAR MEDICINE 14.9(2010):2281-2291. |
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