Endothelin-1 induces vascular endothelial growth factor synthesis in osteoblasts Involvement of p38 mitogen-activated protein kinase

Kozawa, Osamu; Kawamura, Hidenori; Hatakeyama, Daijiro; Matsuno, Hiroyuki

doi:10.1016/s0898-6568(00)00061-9

Cited by 31 publications

(18 citation statements)

References 26 publications

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“…It can also protect cancer cells from paclitaxel-induced apoptosis (41). ET-1 stimulates vascular endothelial growth factor (VEGF) synthesis via osteoblast-like MC3T3-E1 (42). Future investigation is needed to define the role of ET-1 in these steps of the metastastic cascade.…”

Section: Discussionmentioning

confidence: 99%

A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases

Yin

Mohammad

Käkönen

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

349

215

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O steoblastic metastases occur in advanced cases of prostate cancer and frequently in breast cancer (1). Many factors have been proposed to cause disorganized new bone formation at sites of metastases, including insulin-like growth factors 1 and 2, transforming growth factor (TGF)-␤, prostate-specific antigen, urokinase-type plasminogen activator, fibroblast growth factors (FGF)-1 and -2, bone morphogenic proteins (BMPs), and, in particular, endothelin-1 (ET-1) (2-7).ET-1 is a potent vasoconstrictor that binds to ET A and ET B receptors with the latter functioning in ligand clearance (8,9). ET-1 is produced by and affects bone cells (10-12). It stimulates mitogenesis in osteoblasts, which express both ET A and ET B receptors (13-15). ET-1 can decrease osteoclast activity and motility (16).The prostate expresses ET-1 ligand and receptors (5-7). Primary and metastatic prostate cancers make 6,17,18), which can stimulate autocrine proliferation and potentiate effects of insulin-like growth factors, platelet-derived growth factor, epidermal growth factor, and FGF-2 (5). ET B receptor expression is decreased in prostate cancer (5). Nelson et al. (6) found that plasma ET-1 concentrations were higher in men with advanced prostate cancer with bone metastases compared with men with organ-confined disease (6). ET-1 concentrations did not correlate to tumor burden in bone. Five human prostate cancer cell lines expressed ET-1 messenger RNA, and ET-1 increased BMP-initiated bone formation (6).Breast cancers also express ET-1 and are the next most common cause of osteoblastic metastases. Breast cancer cells can convert preproET-1 to 20). Thus, substantial data implicate ET-1 in the pathogenesis of osteoblastic metastases, but a causal role for ET-1 in bone metastasis has not been directly tested. Questions remain about the importance of ET-1 on bone formation in vivo and whether ET-1 receptor blockade would decrease osteoblastic metastases.We found three human breast cancer cell lines that produce ET-1 and cause osteoblastic bone metastases. We used nude mice inoculated with ZR-75-1 cells to demonstrate a causal role for ET-1 in osteoblastic metastasis. Endothelin A receptor blockade in this model dramatically decreased metastases and tumor burden in bone. Materials and MethodsCells. ZR-75-1 and T47D were from American Type Culture Collection. C. Kent Osborne (San Antonio, TX) provided MCF-7 and MDA-MB-231. ZR-75-1 and T47D cells were grown in RPMI medium 1640; MDA-MB-231 in DMEM; MCF-7 in Iscove's modified Eagle's medium (IMEM); and BT483, BT549, MDA-MB435s, HS578T, MDA-MB-436, MDA-MB-361 PC-3, DU145, LNCaP, and TSU-Pr1 in 1:1 mixture of F12͞DMEM. All media contained 10% FCS, 1% penicillin͞streptomycin, and 1% nonessential amino acids in a 37°C atmosphere of 5% CO 2 ͞95% air. T47D and MCF-7 culture media were supplemented with insulin. At 80% confluence, 250 l of serum-free media was conditioned in 48-well plates for 48 h, and cells were counted. ET-1 and BQ-123 were from American Peptide (Sunnyvale, CA). New Bone Formation ...

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Section: Discussionmentioning

confidence: 99%

A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases

Yin

Mohammad

Käkönen

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

349

215

View full text Add to dashboard Cite

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“…In the ®rst model, we hypothesize that there is`cross-talk' between signaling pathways so that blocking one of the signaling pathways may a ect the activation of another pathway. Indeed, some recent publications point out that PKC may function upstream of the p38 kinase pathway (Kozawa et al, 2000;Simon et al, 1998). However, it is unlikely that all three pathways (Erk, p38, PKC) are activated in a sequential order.…”

Section: Discussionmentioning

confidence: 99%

Multiple signaling pathways involved in activation of matrix metalloproteinase-9 (MMP-9) by heregulin-β1 in human breast cancer cells

et al. 2001

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Matrix metalloproteinase-9 (MMP-9) plays important roles in tumor invasion and angiogenesis. Secretion of MMP-9 has been reported in various cancer types including lung cancer, colon cancer, and breast cancer. In our investigation of MMP-9 regulation by growth factors, MMP-9 was activated by heregulin-b1 as shown by zymography in both SKBr3 and MCF-7 breast cancer cell lines. Increase in MMP-9 activity was due to increased MMP-9 protein and mRNA levels, which mainly results from transcriptional upregulation of MMP-9 by heregulinb1. Heregulin-b1 activates multiple signaling pathways in breast cancer cells, including Erk, p38 kinase, PKC, and PI3-K pathways. We examined the pathways involved in heregulin-b1-mediated MMP-9 activation using chemical inhibitors that speci®cally inhibit each of these heregulinb1-activated pathways. The PKC inhibitor RO318220 and p38 kinase inhibitor SB203580 completely blocked heregulin-b1-mediated activation of MMP-9. MEK-1 inhibitor PD098059 partially blocked MMP-9 activation, whereas PI3-K inhibitor wortmannin had no e ect on heregulin-b1-mediated MMP-9 activation. Therefore, at least three signaling pathways are involved in the activation of MMP-9 by heregulin-b1. Since MMP-9 is tightly associated with invasion/metastasis and angiogenesis, our studies suggest that blocking heregulin-b1-mediated activation of MMP-9 by inhibiting the related signaling pathways may provide new strategies for inhibition of cancer metastasis and angiogenesis. Oncogene (2001) 20, 8066 ± 8074.

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“…For instance endothelin 1 is a hypoxia inducible HIF-1 target gene (Hieda and GomezSanchez, 1990;Hu et al, 1998) capable of stimulating proliferation and migration, inducing VEGF production (Okuda et al, 1998;Kozawa et al, 2000), and increasing the expression of various proto-oncogenes (Yin et al, 1992;Herman and Simonson, 1995). Interestingly, several of the VHL regulated genes have potential roles in matrix metabolism.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel hypoxia dependent and independent target genes of the von Hippel-Lindau (VHL) tumour suppressor by mRNA differential expression profiling

et al. 2000

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The von Hippel-Lindau tumour suppressor gene (VHL) targets hypoxia inducible factor (HIF)-a subunits for ubiquitin dependent proteolysis. To better understand the role of this and other putative pathways of gene regulation in VHL function we subjected mRNA from VHL defective renal carcinoma cells and transfectants re-expressing a wild type VHL allele to di erential expression pro®ling, and analysed VHL target genes for oxygen regulated expression. Among a group of newly identi®ed VHL target genes the majority but not all were regulated by oxygen, indicating that whilst dysregulation of the HIF system makes a dominant contribution to alterations in transcription, VHL has other in¯uences on patterns of gene expression. Genes newly de®ned as targets of the VHL/hypoxia pathway (conditionally downregulated by VHL in normoxic cells) include aminopeptidase A, collagen type V, alpha 1, cyclin G2, DEC1/Stra13, endothelin 1, low density lipoprotein receptor-related protein 1, MIC2/CD99, and transglutaminase 2. These genes have a variety of functions relevant to tumour biology. However, not all are connected with the promotion of tumour growth, some being pro-apoptotic or growth inhibitory. We postulate that co-ordinate regulation as part of the HIF pathway may explain this paradox, and that evolution of antiapoptotic pathways may be required for tumour growth under VHL-dysregulation. Our results indicate that it will be necessary to consider the e ects of abnormal activity in integral regulatory pathways, as well as the e ects of individual genes to understand the role of abnormal patterns of gene expression in cancer. Oncogene (2000) 19, 6297 ± 6305.

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Endothelin-1 induces vascular endothelial growth factor synthesis in osteoblasts Involvement of p38 mitogen-activated protein kinase

Cited by 31 publications

References 26 publications

A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases

A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases

Multiple signaling pathways involved in activation of matrix metalloproteinase-9 (MMP-9) by heregulin-β1 in human breast cancer cells

Identification of novel hypoxia dependent and independent target genes of the von Hippel-Lindau (VHL) tumour suppressor by mRNA differential expression profiling

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