Hypoxia-induced VEGF enhances tumor survivability via suppression of serumdeprivation-induced apoptosis

Low oxygen and nutrient depletion play critical roles in tumorigenesis, but little is known about how they interact to produce tumor survival and tumo r malignancy. In the present study, we investigated the mechanism underlyin g hypoxia-modulated apoptosis of serum-deprived HepG2 cells, Our results sh owed that hypoxia blocked the apoptosis, which was accompanied with decreas ed 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 a s a survival factor in a self-promoting manner. Data were further supported by results that recombinant human VEGF (rhVEGF) suppressed the serum depri vation-induced apoptosis, and anti-VEGF neutralizing antibody block anti-ap optotic activity of hypoxia, In addition, inhibitors of receptor tyrosine k inase blocked anti-apoptosis of hypoxia, Our study further showed that rhVE GF or hypoxia induced ERK phosphorylation in serum-deprived cells, and that a specific inhibitor of MAPK/ERK, PD98059 eliminated the anti-apoptotic ac tivity of rhVEGF or hypoxia by increasing Bax/Bcl-2 ratio and caspase-3 act ivity. Our data led us to conclude that induction of ERK phosphorylation an d decrease of Bax/Bcl-2 ratio by rhVEGF implies that hypoxia-induced VEGF p revents apoptosis of serum-deprived cells by activating the MAPK/ERK pathwa y. Taken together, we propose that hypoxia enhances survival of nutrient-de pleted tumor cells by reducing susceptibility to apoptosis, which consequen tly leads to tumor malignancy.