Abstract
Low oxygen and nutrient depletion play critical roles in tumorigenesis, but little is known about how they interact to produce tumor survival and tumor malignancy. In the present study, we investigated the mechanism underlying hypoxia-modulated apoptosis of serum-deprived HepG2 cells. Our results showed that hypoxia blocked the apoptosis, which was accompanied with decreased Bax/Bcl-2 ratio, inhibited cytochrome c release, and reduced caspase-3 activity. More importantly, increased expressions of VEGF and its receptor-2 (KDR) under hypoxic/serum-deprived condition suggest that VEGF may act as a survival factor in a self-promoting manner. Data were further supported by results that recombinant human VEGF (rhVEGF) suppressed the serum deprivation-induced apoptosis, and anti-VEGF neutralizing antibody block anti-apoptotic activity of hypoxia. In addition, inhibitors of receptor tyrosine kinase blocked antiapoptosis of hypoxia. Our study further showed that rhVEGF or hypoxia induced ERK phosphorylation in serum-deprived cells, and that a specific inhibitor of MAPK/ERK, PD98059 eliminated the anti-apoptotic activity of rhVEGF or hypoxia by increasing Bax/Bcl-2 ratio and caspase-3 activity. Our data led us to conclude that induction of ERK phosphorylation and decrease of Bax/Bcl-2 ratio by rhVEGF implies that hypoxia-induced VEGF prevents apoptosis of serum-deprived cells by activating the MAPK/ERK pathway. Taken together, we propose that hypoxia enhances survival of nutrient-depleted tumor cells by reducing susceptibility to apoptosis, which consequently leads to tumor malignancy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Apoptosis / physiology*
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Autocrine Communication
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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Caspase 3
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Caspases / metabolism
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Cell Hypoxia / physiology*
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Cell Survival
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Culture Media, Serum-Free / pharmacology*
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Cytochrome c Group / metabolism
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Endothelial Growth Factors / biosynthesis
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Endothelial Growth Factors / genetics
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Endothelial Growth Factors / pharmacology
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Endothelial Growth Factors / physiology*
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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Gene Expression Regulation, Neoplastic* / drug effects
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Genes, bcl-2
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Humans
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Liver Neoplasms / pathology
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Lymphokines / biosynthesis
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Lymphokines / genetics
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Lymphokines / pharmacology
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Lymphokines / physiology*
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology*
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Mitochondria, Liver / enzymology
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / physiology
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
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Receptor Protein-Tyrosine Kinases / biosynthesis
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Receptor Protein-Tyrosine Kinases / drug effects
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / physiology
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Receptors, Growth Factor / biosynthesis
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Receptors, Growth Factor / drug effects
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Receptors, Growth Factor / genetics
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Receptors, Growth Factor / physiology
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Receptors, Vascular Endothelial Growth Factor
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Recombinant Fusion Proteins / pharmacology
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / metabolism
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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bcl-2-Associated X Protein
Substances
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BAX protein, human
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Culture Media, Serum-Free
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Cytochrome c Group
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Endothelial Growth Factors
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Enzyme Inhibitors
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Flavonoids
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Lymphokines
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Neoplasm Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Growth Factor
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Recombinant Fusion Proteins
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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bcl-2-Associated X Protein
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Receptor Protein-Tyrosine Kinases
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Receptors, Vascular Endothelial Growth Factor
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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CASP3 protein, human
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Caspase 3
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Caspases
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one