Different signalling pathways regulate VEGF and IL-8 expression in breast cancer: implications for therapy

Chelouche-Lev, Dina; Miller, Claudia P.; Tellez, Carmen S.; Ruiz, Maribelís; Bar‐Eli, Menashe; Price, Janet E.

doi:10.1016/j.ejca.2004.05.024

Cited by 55 publications

(39 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A number of pathways have been found to be actively involved in the modulation of IL-8 production, including MAPKs, JAK2, and PI3K/Akt pathways (21,25,(42)(43)(44). In agreement with those studies, our results showed that the activation of ERK1/2, SAPK/JNK, p38 MAPK, JAK2, p85 PI3K, AP-1 and p65 NF-κB pathways was closely associated with the constitutive IL-8 secretion in MDA-MB-231 cells (Fig.…”

Section: Discussionsupporting

confidence: 81%

Berberine hydrochloride IL-8 dependently inhibits invasion and IL-8-independently promotes cell apoptosis in MDA-MB-231 cells

Zhao

Shi

et al. 2014

Oncology Reports

View full text Add to dashboard Cite

Abstract. Breast cancer, the leading cause of cancer-related mortality worldwide in females, has high metastastic and recurrence rates. The aim of the present study was to evaluate the anti-metastatic and anticancer in situ effect of berberine hydrochloride (BER) in MDA-MB-231 cells. BER dose-dependently inhibited proliferation and the IL-8 secretion of MDA-MB-231 cells. Additional experiments revealed that the inactivation of PI3K, JAK2, NF-κB and AP-1 by BER contributed to the decreased IL-8 secretion. BER abrogated cell invasion induced by IL-8 accompanied with the downregulation of the gene expression of MMP-2, EGF, E-cadherin, bFGF and fibronectin.In addition, BER reduced cell motility but induced G2/M arrest and cell apoptosis in an IL-8-independent manner. BER modulated multiple signaling pathway molecules involved in the regulation of cell apoptosis, including activation of p38 MAPK and JNK and deactivation of JAK2, p85 PI3K, Akt and NF-κB. The enhanced cell apoptosis induced by BER was eliminated by inhibitors of p38 MAPK and JNK but was strengthened by activator of p38 MAPK. Thus, BER inhibited cell metastasis partly through the IL-8 mediated pathway while it induced G2/M arrest and promoted cell apoptosis through the IL-8 independent pathway. Apoptosis induced by BER was mediated by crosstalks of various pathways including activation of p38 MAPK and JNK pathways and inactivation of JAK2/ PI3K/NF-κB/AP-1 pathways. The results suggested that BER may be an efficient and safe drug candidate for treating highly metastatic breast cancer.

show abstract

Section: Discussionsupporting

confidence: 81%

Berberine hydrochloride IL-8 dependently inhibits invasion and IL-8-independently promotes cell apoptosis in MDA-MB-231 cells

Zhao

Shi

et al. 2014

Oncology Reports

View full text Add to dashboard Cite

show abstract

“…Our results demonstrated that the effect of bcl-2 overexpression on VEGF expression, ERK and AKT phosphorylation, and on the response to PI3K and MAPK inhibitors was strictly dependent on the oxygen concentration. In fact, all of these parameters were similar in the control and bcl-2-overexpressing cells exposed to normoxic conditions, and as reported for other tumor histotypes (Chelouche-Lev et al, 2004), both PI3K and MAPK pathways were essential for the constitutive expression of VEGF in normoxia. On the contrary, under hypoxic conditions increased VEGF secretion, AKT and ERK phosphorylation were evidenced in both transiently and stably bcl-2-overexpressing cells.…”

supporting

confidence: 48%

Involvement of PI3K and MAPK Signaling in bcl-2-induced Vascular Endothelial Growth Factor Expression in Melanoma Cells

Trisciuoglio¹,

Iervolino²,

Zupi³

et al. 2005

MBoC

View full text Add to dashboard Cite

We have previously demonstrated that bcl-2 overexpression in tumor cells exposed to hypoxia increases the expression of vascular endothelial growth factor (VEGF) gene through the hypoxia-inducible factor-1 (HIF-1). In this article, we demonstrate that exposure of bcl-2 overexpressing melanoma cells to hypoxia induced phosphorylation of AKT and extracellular signal-regulated kinase (ERK)1/2 proteins. On the contrary, no modulation of these pathways by bcl-2 was observed under normoxic conditions. When HIF-1␣ expression was reduced by RNA interference, AKT and ERK1/2 phosphorylation were still induced by bcl-2. Pharmacological inhibition of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways reduced the induction of VEGF and HIF-1 in response to bcl-2 overexpression in hypoxia. No differences were observed between control and bcl-2-overexpressing cells in normoxia, in terms of VEGF protein secretion and in response to PI3K and MAPK inhibitors. We also demonstrated that RNA interference-mediated down-regulation of bcl-2 expression resulted in a decrease in the ERK1/2 phosphorylation and VEGF secretion only in bcl-2-overexpressing cell exposed to hypoxia but not in control cells. In conclusion, our results indicate, for the first time, that bcl-2 synergizes with hypoxia to promote expression of angiogenesis factors in melanoma cells through both PI3K-and MAPK-dependent pathways. INTRODUCTIONAngiogenesis is a complex and multilevel process of new capillary formation on the basis of already existing blood vessels. Physiologically, it is a very strictly regulated process, which results in a balance between stimulatory (angiogenic) and inhibitory (angiostatic) factors to control the correct development of blood vessels. Angiogenesis is a rate-limiting step in tumor growth and progression, and many tumors develop a severely hypoxic microenvironment and secrete angiogenesis-stimulating factors (Folkman et al., 1971;Talks et al., 2000). Vascular endothelial growth factor (VEGF), a potent and specific mitogen for vascular endothelial cells, is a critical mediator of angiogenesis. Its expression is induced in cancer cells as a result of hypoxia and multiple genetic alterations, including p53 and PTEN loss-of-function, RAS and SRC gain-of-function, and autocrine tyrosine kinase signaling pathways (Mukhopadhyay et al., 1995;Arbiser et al., 1997;Petit et al., 1997;Akagi et al., 1998;Ellis et al., 1998;Yen et al., 2000). Based on the analysis of melanoma and breast cancer cells recently reported by our group Iervolino et al., 2002;Del Bufalo et al., 2003;Trisciuoglio et al., 2004), this list can now be extended to include the increased VEGF expression resulting from bcl-2 overexpression. Hypoxia-and growth factor-induced VEGF expression in tumor cells is regulated by the hypoxia inducible factor 1 (HIF-1) (Jiang et al., 1997;Mazure et al., 1997;Ravi et al., 2000;Zhong et al., 2000;Zundel et al., 2000;Laughner et al., 2001;Fukuda et al., 2002), a transcription factor that is compose...

show abstract

“…However, the signaling pathways that regulate VEGF expression remain controversial. The p21-activated kinase-1 (PAK-1), phosphatidylinositol 3 0 -kinase (PI3K), and mitogen-activated protein (MAP) kinases signaling pathways have all been implicated in the regulation of VEGF expression in breast cancer cells in different studies (Bagheri-Yarmand et al, 2000;Xiong et al, 2001;Chelouche-Lev et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Both tumor cells and tumorassociated neutrophils and macrophages have been reported to release IL-8, which contributes to accelerated tumor growth and poor survival (Chen et al, 2003). The PI3K pathway has been implicated in regulation of IL-8 expression (Chelouche-Lev et al, 2004). Hypoxia in solid tumors also stimulates the expression of both IL-8 and VEGF, and VEGF can further enhance IL-8 expression (Rofstad and Halsor, 2002).…”

Section: Introductionmentioning

confidence: 99%

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

et al. 2006

View full text Add to dashboard Cite

We determined the impact of HER2 signaling on two proangiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), and on an antiangiogenic factor, thrombospondin-1 (TSP-1). Re-expression of HER2 in MCF-7 and T-47D breast cancer cells that endogenously express low levels of HER2 resulted in elevated expression of VEGF and IL-8 and decreased expression of TSP-1. Inhibition of HER2 with a humanized anti-HER2 antibody (trastuzumab, or Herceptin s ) or a retrovirus-mediated small interfering RNA against HER2 (siHER2) decreased VEGF and IL-8 expression, but increased TSP-1 expression in BT474 breast cancer cells that express high levels of HER2. These in vitro results were further evaluated by treatment of BT474 xenografts in immunosuppressed mice with trastuzumab. Trastuzumab inhibited growth of BT474 xenografts and decreased microvascular density associated with downregulation of VEGF and IL-8 and with upregulation of TSP-1 expression. Inhibiting the PI3K-AKT pathway decreased VEGF and IL-8 expression. AKT1 overexpession increased VEGF and IL-8 expression, but did not increase TSP-1 expression. A p38 kinase inhibitor, SB203580, instead blocked TSP-1 expression and a p38 activator, MKK6, increased TSP-1 expression. Trastuzumab stimulated sustained p38 activation and SB203580 attenuated the TSP-1 upregulation induced by trastuzumab. HER2 signaling therefore influences the equilibrium between pro-and antiangiogenic factors via distinct signaling pathways. Trastuzumab inhibits angiogenesis and tumor growth, at least in part, through activation of the HER2-p38-TSP-1 pathway and inhibition of the HER2-PI3K-AKT-VEGF/IL-8 pathway.

show abstract

Different signalling pathways regulate VEGF and IL-8 expression in breast cancer: implications for therapy

Cited by 55 publications

References 31 publications

Berberine hydrochloride IL-8 dependently inhibits invasion and IL-8-independently promotes cell apoptosis in MDA-MB-231 cells

Berberine hydrochloride IL-8 dependently inhibits invasion and IL-8-independently promotes cell apoptosis in MDA-MB-231 cells

Involvement of PI3K and MAPK Signaling in bcl-2-induced Vascular Endothelial Growth Factor Expression in Melanoma Cells

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

Contact Info

Product

Resources

About