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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]

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