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

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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).

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