QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 16, Issue 9, 4153-4162, September 2005

This Article Full Text Full Text (PDF) All Versions of this Article: E04-12-1087v1 16/9/4153    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Trisciuoglio, D. Articles by Del Bufalo, D. Search for Related Content PubMed PubMed Citation Articles by Trisciuoglio, D. Articles by Del Bufalo, D.

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

Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, 00158 Rome, Italy

Submitted December 17, 2004; Accepted June 16, 2005
Monitoring Editor: Gerard Evan

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.

Abbreviations used: ERK1/2, extracellular signal-regulated kinase 1/2; HIF-1, hypoxia-inducible factor-1; HRE, hypoxic responsive element; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; VEGF, vascular endothelial growth factor; Wort, wortmannin.

^* These authors contributed equally to this work.

Address correspondence to: Donatella Del Bufalo (delbufalo{at}ifo.it).

This article has been cited by other articles:

				S. Giorgini, D. Trisciuoglio, C. Gabellini, M. Desideri, L. Castellini, C. Colarossi, U. Zangemeister-Wittke, G. Zupi, and D. Del Bufalo Modulation of bcl-xL in Tumor Cells Regulates Angiogenesis through CXCL8 Expression Mol. Cancer Res., August 1, 2007; 5(8): 761 - 771. [Abstract] [Full Text] [PDF]

				Q. Zhou, L.-Z. Liu, B. Fu, X. Hu, X. Shi, J. Fang, and B.-H. Jiang Reactive oxygen species regulate insulin-induced VEGF and HIF-1{alpha} expression through the activation of p70S6K1 in human prostate cancer cells Carcinogenesis, January 1, 2007; 28(1): 28 - 37. [Abstract] [Full Text] [PDF]

				S. Venkatesha, J.-i. Hanai, P. Seth, S. A. Karumanchi, and V. P. Sukhatme Lipocalin 2 Antagonizes the Proangiogenic Action of Ras in Transformed Cells Mol. Cancer Res., November 1, 2006; 4(11): 821 - 829. [Abstract] [Full Text] [PDF]

				B. D. Zeitlin, E. Joo, Z. Dong, K. Warner, G. Wang, Z. Nikolovska-Coleska, S. Wang, and J. E. Nor Antiangiogenic Effect of TW37, a Small-Molecule Inhibitor of Bcl-2. Cancer Res., September 1, 2006; 66(17): 8698 - 8706. [Abstract] [Full Text] [PDF]

				G. Melillo and G. L. Semenza Meeting Report: Exploiting the Tumor Microenvironment for Therapeutics. Cancer Res., May 1, 2006; 66(9): 4558 - 4560. [Abstract] [Full Text] [PDF]