Involvement of PI3K and MAPK signaling in bcl-2-induced vascular endothelial growth factor expression in melanoma cells

Daniela Trisciuoglio, Angela Iervolino, Gabriella Zupi, Donatella Del Bufalo

Research output: Contribution to journalArticle

78 Citations (Scopus)

Abstract

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-1α 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.

Original languageEnglish
Pages (from-to)4153-4162
Number of pages10
JournalMolecular Biology of the Cell
Volume16
Issue number9
DOIs
Publication statusPublished - Sep 2005

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Phosphatidylinositol 3-Kinase
Mitogen-Activated Protein Kinases
Vascular Endothelial Growth Factor A
Melanoma
Hypoxia-Inducible Factor 1
Phosphorylation
RNA Interference
Cell Hypoxia
Mitogen-Activated Protein Kinase 3
Angiogenesis Inducing Agents
Mitogen-Activated Protein Kinase 1
Protein Kinase Inhibitors
Proteins
Down-Regulation
Pharmacology
Hypoxia
Genes
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Involvement of PI3K and MAPK signaling in bcl-2-induced vascular endothelial growth factor expression in melanoma cells. / Trisciuoglio, Daniela; Iervolino, Angela; Zupi, Gabriella; Del Bufalo, Donatella.

In: Molecular Biology of the Cell, Vol. 16, No. 9, 09.2005, p. 4153-4162.

Research output: Contribution to journalArticle

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