Diosgenin Induces Hypoxia-Inducible Factor-1 Activation and Angiogenesis through Estrogen Receptor-Related Phosphatidylinositol 3-kinase/Akt and p38 Mitogen-Activated Protein Kinase Pathways in Osteoblasts

Yen, Men‐Luh; Su, Jen Liang; Chien, Chung‐Liang; Tseng, Kuang Wen; Yang, Ching-Yao; Chen, Wei Fang; Chang, Che‐Cheng; Kuo, Min-Liang

doi:10.1124/mol.104.010082

Cited by 80 publications

(51 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our experiments with protein kinase inhibitors (MEK/ERK1/2, p38 kinase, and PI3-K/Akt pathways) also suggest for the first time that xenoestrogens induce the VEGF response in MELN cells via specific kinase pathways. These kinase pathways have previously been shown to play a role in regulating VEGF expression in response to growth factors (Maity et al 2000, Milanini-Mongiat et al 2002, diosgenin (Yen et al 2005), and androgens (Mabjeesh et al 2003), in agreement with this study. In addition, non-genomic actions for E 2 or xenoestrogens at low concentrations through the rapid activation of signal cascade emanating from the membrane have also been described (Nadal et al 2000, Zivadinovic & Watson 2005.…”

Section: Discussionsupporting

confidence: 82%

“…VEGF promoter is complex with multiple consensus sequences for different transcription factors (Tischer et al 1991). Attempts to identify the sites through which ERs act to induce VEGF expression have involved an ERE (Hyder et al 2000, Mueller et al 2000, or interaction of ER with other transcription factors such SP1/3 sites (Stoner et al 2004) and the hypoxiaresponsive element (Kazi et al 2005), or through activation of kinase cascade pathways (Yen et al 2005), depending on the nature of cells and the microenvironment including hypoxia/ normoxia, the estrogenic medium and differential expression of other nuclear factors. Preliminary experiments indicate that BPA, OP, dieldrin, and BBP do not increase VEGF induction in hypoxia conditions in MELN (high levels of HIF-1a (personal data)).…”

Section: Discussionmentioning

confidence: 99%

“…Preliminary data from our laboratory indicate that BPA and OP increase VEGF transcription in MCF-7 and ERatransfected MDA-MB-231 cells (data not shown), through complex mechanisms involving interaction of ER with VEGF promoter sequences, as already described for E 2 . Recently, alternative signaling pathways, such as the mitogen-activated protein kinase, the p38 kinase, and phosphatidylinositol-3-kinase (PI3-K), have also been implicated in ER-mediated VEGF regulation (Kazi et al 2005, Yen et al 2005.…”

Section: Xenoestrogens Stimulate Vegf Expression Via Multiple Kinasesmentioning

confidence: 99%

See 2 more Smart Citations

Xenoestrogens modulate vascular endothelial growth factor secretion in breast cancer cells through an estrogen receptor-dependent mechanism

Buteau-Lozano¹,

Velasco²,

Cristofari³

et al. 2007

Journal of Endocrinology

120

View full text Add to dashboard Cite

Environmental chemicals may affect human health by disrupting endocrine function. Their possible role in the mammary gland and breast tumors is still unknown. Previous studies have demonstrated that vascular endothelial growth factor (VEGF), a key factor in angiogenesis and tumor progression, is an estrogenregulated gene. We analyzed whether VEGF expression is regulated by different xenoestrogens in several breast cancer cells, MELN (derived from MCF-7) and MELP (derived from MDA-MB-231) and stably expressing estrogen receptor a (ERa); these cell lines stably express estrogen response element (b-globin)-luciferase. Genistein, bisphenol A (BPA), 4-(tert-octyl)phenol (OP), dieldrin, and several phthalates, including benzyl butyl phthalate (BBP) and di-ethyl-2-hexyle phthalate (DEHP), were first shown to be estrogenic. These compounds induced a dosedependent increase of VEGF secretion in MELN and MCF-7 cells; maximal effect was observed at 1-10 mM non-cytotoxic concentrations and was inhibited by the antiestrogen ICI 182 780. VEGF increase was not observed in ERa-negative MDA-MB-231 cells. Most substances increased VEGF transcript levels in MELN cells. In contrast, g-hexachlorocyclohexane, vinclozolin, and the phthalates (mono-n-butyl ester phthalic acid, di-isononyle phthalate, and di-isodecyle phthalate) were ineffective on both VEGF secretion and estrogenic luciferase induction in these cell lines. Specific kinase inhibitors PD98059, SB203580, or LY294002 suppressed the xenoestrogen-induced VEGF response, suggesting activation of MEK, p38 kinase, and phosphatidylinositol-3-kinase pathways. Our in vitro results show for the first time that genistein and xenoestrogens (BPA, OP, dieldrin, BBP, and DEHP at high concentrations) up-regulate VEGF expression in MELN cells by an ER-dependent mechanism. Since VEGF increases capillary permeability and breast tumor angiogenesis in vivo, the physiological relevance of these findings is discussed.

show abstract

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Xenoestrogens Stimulate Vegf Expression Via Multiple Kinasesmentioning

confidence: 99%

See 1 more Smart Citation

Xenoestrogens modulate vascular endothelial growth factor secretion in breast cancer cells through an estrogen receptor-dependent mechanism

Buteau-Lozano¹,

Velasco²,

Cristofari³

et al. 2007

Journal of Endocrinology

120

View full text Add to dashboard Cite

show abstract

“…Increased p38 signaling has been found in a HER2-driven tamoxifen-resistant mouse model (6). Moreover, HER2 has been reported to regulate VEGF production in human breast cancer cell lines and tumors (25), and VEGF signaling has been shown to contribute to a highly proliferating, aggressive phenotype in these tumors (14,15). However, VEGF is also expressed in a considerable number of HER2-negative tumors, suggesting that other signaling pathways may drive its expression (14,15).…”

Section: Discussionmentioning

confidence: 99%

An Autocrine VEGF/VEGFR2 and p38 Signaling Loop Confers Resistance to 4-Hydroxytamoxifen in MCF-7 Breast Cancer Cells

Aesöy

Sanchez

Norum

et al. 2008

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…IL-1 treatment, which is known to induce MAPK phosphorylation (34), served as a positive control. Recently, Yen et al (35) reported that diosgenin promoted angiogenesis in pre-osteoblast-like cells by a hypoxia-inducible factor-1· dependent mechanism involving the activation of p38 MAPK. Our recent study showed that, diosgenin (40 μM) inhibited ERK activation but activated p38 and JNK in human erythroleukemia (HEL) cells (28).…”

Section: Discussionmentioning

confidence: 99%

MAP kinase subtypes and Akt regulate diosgenin-induced apoptosis of rheumatoid synovial cells in association with COX-2 expression and prostanoid production

Liagre¹,

Léger²,

Vergne-Salle³

et al. 2007

Int J Mol Med

View full text Add to dashboard Cite

Abstract. In the present study, we investigated the signalling pathways involved in diosgenin-induced apoptosis in human rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) in vitro with particular interest on Akt and MAPKs activation in relation to arachidonic acid metabolism via COX-2 pathway. MAPK activation was measured by ELISA quantification in diosgenin-treated human RA FLS. Expression of Akt and phospho-Akt was analyzed by Western blot analysis. Nuclear factor-κB (NF-κB) translocation was evaluated by electromobility shift assay. The prostanoid production (COX-2 activity) was measured by quantitative ELISA. Diosgenininduced apoptosis in the presence of MAPK or Akt inhibitors was detected by a quantitative determination of DNA fragmentation. Treatment of human RA FLS with 40 μM diosgenin caused an activation of p38 and JNK and an inhibition of ERK phosphorylation. Akt and NF-κB are potentially required for diosgenin-induced apoptosis in human RA FLS because 40 μM diosgenin abrogated Akt phosphorylation which correlated with an inhibition of NF-κB nuclear translocation. SB203580 and SP600125 (p38 and JNK inhibitors) reduced diosgenininduced DNA fragmentation whereas U0126 and LY294002 (MEK and PI3 kinase/Akt inhibitors) caused an amplification of proapoptotic effect of diosgenin. Diosgenin increased COX-2 activity resulting in PGE 2 and 6-keto-PGF 1· overproduction in human RA FLS. All MAPK inhibitors markedly reduced diosgenin-induced PGE 2 and 6-keto-PGF 1· synthesis except for SP600125 on 6-keto-PGF 1· production. These results provide, for the first time, strong evidence that a combined association implicating a MEK inhibitor (U0126) and diosgenin is the most effective in inducing very strong apoptosis with down-regulation of COX-2 expression and activity in human RA FLS.

show abstract

Diosgenin Induces Hypoxia-Inducible Factor-1 Activation and Angiogenesis through Estrogen Receptor-Related Phosphatidylinositol 3-kinase/Akt and p38 Mitogen-Activated Protein Kinase Pathways in Osteoblasts

Cited by 80 publications

References 37 publications

Xenoestrogens modulate vascular endothelial growth factor secretion in breast cancer cells through an estrogen receptor-dependent mechanism

Xenoestrogens modulate vascular endothelial growth factor secretion in breast cancer cells through an estrogen receptor-dependent mechanism

An Autocrine VEGF/VEGFR2 and p38 Signaling Loop Confers Resistance to 4-Hydroxytamoxifen in MCF-7 Breast Cancer Cells

MAP kinase subtypes and Akt regulate diosgenin-induced apoptosis of rheumatoid synovial cells in association with COX-2 expression and prostanoid production

Contact Info

Product

Resources

About