Apigenin suppresses the expression of VEGF, an important factor for angiogenesis, in endothelial cells via degradation of HIF‐1α protein

Osada, Mayuko; Imaoka, Shingi; Funae, Yoshihiko

doi:10.1016/j.febslet.2004.08.036

Cited by 119 publications

(67 citation statements)

References 30 publications

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“…A recently published study indeed showed that a much higher concentration of apigenin inhibited HIF-1 activity through inhibition of HIF-1a stabilization. 57 However, as we worked with lower concentrations of apigenin, the results described here are probably more physiologic.…”

Section: Discussionmentioning

confidence: 81%

Role for casein kinase 2 in the regulation of HIF‐1 activity

Mottet

Ruys

Demazy

et al. 2005

Intl Journal of Cancer

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Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that plays a major role in cellular adaptation to hypoxia. The mechanisms regulating HIF-1 activity occurs at multiple levels in vivo. The HIF-1a subunit is highly sensible to oxygen and is rapidly degraded by the proteasome 26S in normoxia. Activation in hypoxia occurs through a multistep process including inhibition of HIF-1a degradation, but also increase in the transactivation activity of HIF-1. Several data indicate that phosphorylation could play a role in this regulation. In this report, we investigated the role of casein kinase 2 (CK2), an ubiquitous serine/ threonine kinase, in the regulation of HIF-1 activity. Hypoxia was capable of increasing the expression of the b subunit of CK2, of inducing a relocalization of this subunit at the plasma membrane, of inducing nuclear translocation of the a subunit and of increasing CK2 activity. Three inhibitors of this kinase, DRB (5,6-dichloro-1-b-D-ribofuranosyl-benzimidazole), TBB (4,5,6,7-tetrabromotriazole) and apigenin, as well as overexpression of a partial dominant negative mutant of CK2a, were shown to inhibit HIF-1 activity as measured by a reporter assay and through hypoxiainduced VEGF and aldolase expression. This does not occur at the stabilization process since they did not affect HIF-1a protein level. DNA-binding activity was also not inhibited. We conclude that CK2 is an important regulator of HIF-1 transcriptional activity but the mechanism of this regulation remains to be determined. Since HIF-1 plays a major role in tumor angiogenesis and since CK2 has been described to be overexpressed in tumor cells, this new pathway of regulation can be one more way for tumor cells to survive. ' 2005 Wiley-Liss, Inc.Key words: casein kinase 2; HIF-1; neoangiogenesis HIF-1 (hypoxia-inducible factor-1) is a key regulator of cell response to reduced oxygen level. In response to hypoxic conditions, HIF-1 increases the expression of downstream target genes such as erythropoietin (EPO), vascular endothelial growth factor (VEGF) and glycolytic enzymes (aldolase A, enolase-a) and mediates adaptation of cells to decreased oxygen level. 1 The role of HIF-1 in the regulation of tumor growth by hypoxia via the initiation of angiogenesis is certainly the best example of such an adaptive response. 2 Oncogene activation and tumor-suppressor inactivation result in deregulated cellular proliferation. However, most tumors grown larger than 1 mm 3 contain regions of low oxygen tension (hypoxia) due to an imbalance between oxygen supply and consumption. Formation of new blood vessels or ''neoangiogenesis'' is thus essential for further tumor growth. It is also important to allow tumor cell dissemination at distant sites, i.e., metastasis.Several studies using HIF-1 mutant cells have shown that HIF-1 has a profound effect on tumor biology. For example, tumors grown from HIF-1a-defective embryonic stem cells display abnormal vascularity and reduced growth rate. 3 Moreover, HIF-1 is upregulated in a broad r...

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Section: Discussionmentioning

confidence: 81%

Role for casein kinase 2 in the regulation of HIF‐1 activity

Mottet

Ruys

Demazy

et al. 2005

Intl Journal of Cancer

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“…To investigate the lower limit of oxygen concentrations where C. glutamicum can grow, we used simple anaerobic and microaerobic culture systems, Anaero Pack, as has often been reported (Yano et al 2002;Osada et al 2004;Hagiwara et al 2006). By applying the systems, four representative wild-type strains of C. glutamicum, ATCC 13032, ATCC 14067, ATCC 13869, and ATCC 13870, were examined for their colony-forming abilities on BY agar plates under several oxygen concentrations (0%, 0.5%, 3%, 6%, and atmospheric conditions 21%) in a sealed 2.5-liter box.…”

Section: Resultsmentioning

confidence: 99%

Anaerobic growth and potential for amino acid production by nitrate respiration in Corynebacterium glutamicum

Takeno

Ohnishi

Komatsu

et al. 2007

Appl Microbiol Biotechnol

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Oxygen limitation is a crucial problem in amino acid fermentation by Corynebacterium glutamicum. Toward this subject, our study was initiated by analysis of the oxygen-requiring properties of C. glutamicum, generally regared as a strict aerobe. This organism formed colonies on agar plates up to relatively low oxygen concentrations (0.5% O2), while no visible colonies were formed in the absence of O2. However, in the presence of nitrate (NO3¯), the organism exhibited limited growth anaerobically with production of nitrite (NO2¯), indicating that C. glutamicum can use nitrate as a final electron acceptor.Assays of cell extracts from aerobic and hypoxic cultures yielded comparable nitrate reductase activities, irrespective of nitrate levels. Genome analysis revealed a narK2GHJIcluster potentially relevant to nitrate reductase and transport. Disruptions of narG and narJ abolished the nitrate-dependent anaerobic growth with the loss of nitrate reductase activity. Disruption of the putative nitrate:nitrite antiporter gene narK2 did not affect the enzyme activity but impaired the anaerobic growth. These indicate that this locus is responsible for nitrate respiration. Agar piece assays using L-lysine-and L-arginine-producing strains showed that production of both amino acids occurred anaerobically by nitrate respiration, indicating the potential of C. glutamicum for anaerobic amino acid production.

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“…Thus, it is conceivable that chrysin may also inhibit HIF-1a via AKT signaling. It was reported that flavonoids or related compounds, such as apigenin (28,46), resveratrol (47), and (À)-epigallocatechin-3-gallate (48), inhibited expression of HIF-1a through multiple pathways, including protein synthesis and protein degradation. Consistent with previous reports, we show here that chrysin is also multifunctioning in HIF-1a pathway.…”

Section: Discussionmentioning

confidence: 99%

Chrysin inhibits expression of hypoxia-inducible factor-1α through reducing hypoxia-inducible factor-1α stability and inhibiting its protein synthesis

Xue

et al. 2007

Molecular Cancer Therapeutics

161

107

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Chrysin is a natural flavonoid and has been shown recently to have anticancer effects. However, the mechanisms that chrysin inhibits cancers are not well known. In this study, we investigated the effects of chrysin on expression of hypoxia-inducible factor-1A (HIF-1A) and vascular endothelial growth factor in human prostate cancer DU145 cells. Chrysin inhibited insulin-induced expression of HIF-1A by reducing its stability. Chrysin increases ubiquitination and degradation of HIF-1A by increasing its prolyl hydroxylation. In addition, chrysin interfered with interaction between HIF-1A and heat shock protein 90. Chrysin was also found to inhibit HIF-1A expression through AKT signaling. Inhibition of HIF-1A by chrysin resulted in abrogation of vascular endothelial growth factor expression. Finally, we showed that chrysin inhibited DU145 xenograft-induced angiogenesis in nude mice. Taken together, these results suggest that chrysin is a potent inhibitor of HIF-1A and provide a new sight into the mechanisms of chrysin against cancers. [Mol Cancer Ther 2007;6(1):220 -6]

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Apigenin suppresses the expression of VEGF, an important factor for angiogenesis, in endothelial cells via degradation of HIF‐1α protein

Cited by 119 publications

References 30 publications

Role for casein kinase 2 in the regulation of HIF‐1 activity

Role for casein kinase 2 in the regulation of HIF‐1 activity

Anaerobic growth and potential for amino acid production by nitrate respiration in Corynebacterium glutamicum

Chrysin inhibits expression of hypoxia-inducible factor-1α through reducing hypoxia-inducible factor-1α stability and inhibiting its protein synthesis

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