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MFTZ-1 reduces constitutive and inducible HIF-1? accumulation and VEGF secretion independent of its topoisomerase II inhibition.

ABSTRACT: 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? (HIF-1?) accumulation, vascular endothelial growth factor (VEGF) secretion and angiogenesis. MFTZ-1 reduced HIF-1? 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? protein or the level of HIF-1? 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?-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?-independent VEGF secretion and concurrently antagonize inducible, HIF-1?-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? or Top2-defective HL60/MX2 cells, we showed that MFTZ-1 affected HIF-1? 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? accumulation and VEGF secretion possibly via PI3K-Akt and MAPK pathways, eliciting anti-angiogenesis independently of its Top2 inhibition.

SUBMITTER: Dai M

PROVIDER: S-EPMC3822569 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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MFTZ-1 reduces constitutive and inducible HIF-1α accumulation and VEGF secretion independent of its topoisomerase II inhibition.

Dai Mei M Miao Ze-Hong ZH Ren Xuan X Tong Lin-Jiang LJ Yang Na N Li Ting T Lin Li-Ping LP Shen Yue-Mao YM Ding Jian J

Journal of cellular and molecular medicine 20100901 9

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-1α (HIF-1α) accumulation, vascular endothelial growth factor (VEGF) secretion and angiogenesis. MFTZ-1 reduced HIF-1α accumulation driven by hypoxia or growth factors in human cancer cells. Mechanistic studies revealed that MFTZ-1 did not affect the degradation o ...[more]

PMID: 19538463

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Project description:Hypoxia-inducible factors (HIFs) play an important role in mediating the physiological response to low oxygen environments. However, whether the expression of HIFs changes with age is unknown. In the present study, the effect of aging on HIF-1?, HIF-2?, HIF-3? and VEGF expression in the heart and lung of 30 Tibetan sheep that were adapted to hypoxia was evaluated. The 30 sheep were subdivided into groups of 10 animals that were 1, 2 or 6 years of age. Immunohistochemistry for HIF-1?, HIF-2?, HIF-3? and VEGF revealed that the immunostaining intensity of VEGF protein in the heart and lung was significantly higher than the intensity of immunostaining against the HIFs (p < 0.05). HIF-1? and HIF-2? protein translocated into the nucleus of cardiac muscle cells. However, immunostaining for HIF-3? was restricted to the cytoplasm of the myocardial cells. Immunostaining for HIF-1?, HIF-2?, HIF-3? and VEGF was detected within alveolar macrophages. The concentration of HIF-1? and HIF-2? was higher in the lung of 1-year-old than 6-year-old sheep (p < 0.05). In contrast, HIF-3? and VEGF immunostaining was most prominent in the hearts of the oldest sheep. However, when RT-PCR was used to evaluate RNA within the tissues, the expression of all four studied genes was higher in the lung than in the heart in the 1-year-old sheep (p < 0.05). Furthermore, VEGF and HIF-3? gene expression was higher in the heart from 1-year old than 6-year old sheep (p < 0.05). However, in the lung, HIF-1? and HIF-2? gene expression was lower in 1-year old than 6-year old sheep (p < 0.05). We conclude that HIF-3? and VEGF may play be important in how the heart responds to hypoxia. Additionally, HIF-1? and HIF-2? may have a role in the adaptation of the lung to hypoxia. The expression of these proteins in alveolar macrophages suggests a potential role of these cells in the physiological response to hypoxia. These results are useful in understanding how age influences the hypoxia adaption mechanisms of the heart and lung and may help to better understand chronic mountain sickness that is commonly observed in Tibetan people living on the Qinghai-Tibetan plateau.

Dataset Information

MFTZ-1 reduces constitutive and inducible HIF-1? accumulation and VEGF secretion independent of its topoisomerase II inhibition.

Publications

MFTZ-1 reduces constitutive and inducible HIF-1α accumulation and VEGF secretion independent of its topoisomerase II inhibition.

Similar Datasets

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