Hypoxia-induced VEGF enhances tumor survivability via suppression of serum deprivation-induced apoptosis

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 deprivationinduced 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 speci®c 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 hypoxiainduced 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. Oncogene (2000) 19, 4621 ± 4631.

Phosphorylated KDR expression in endometrial cancer cells relates to HIF1α/VEGF pathway and unfavourable prognosis

“…[26][27][28][29] Whether such an autocrine loop functions as a stimulus for cancer cell proliferation, resistance to apoptotic stimuli or through some other process remains obscure. [30][31][32][33] Nevertheless, expression of pKDR was associated significantly with poor prognosis of stage I patients. Histological grade was also a significant independent variable of prognosis, while depth of myometrial invasion and lympho-vascular space invasion did not reach significance.…”

Antiapoptotic action of hypoxia-inducible factor-1α in human endothelial cells

“…25 Further evidence supporting an antiapoptotic role for HIF-1a was demonstrated when neutralizing antibody against vascular endothelial growth factor (VEGF), the major target gene protein transactivated by HIF-1, was shown to block the antiapoptotic effect of hypoxia on HepG2 cells. 26 Caution should, however, be exercised when interpreting these studies since they were based on indirect evidence obtained from mutant cell lines, 24 from studies of downstream target proteins such as VEGF, 26 or from the use of chemical inducers of HIF-1a such as CoCl 2 25 that, by themselves, can induce apoptosis. 27,28 In the current study, we used the technique of RNAi to evaluate the role of HIF-1a in modulating anoxia-induced apoptotic injury in primary cultured HUVECs.…”

A Novel Role for Vascular Endothelial Growth Factor as an Autocrine Survival Factor for Embryonic Stem Cells during Hypoxia

“…Growth factors may also protect cells against apoptosis in response to other stimuli, as exemplified by the ability of erythropoietin, c-kit ligand, or interleukin-3 to block p53-mediated apoptosis of hematopoietic cell lines (50 -52) by the protective effect of IGF-I or EGF on epithelial cells or lymphocytes against Fas-induced apoptosis (53)(54)(55) or by the inhibition by IGF-I of glutamateinduced apoptosis of oligodendrocyte progenitors (56). In addition, IGF-1 and PDGF inhibit apoptosis of fibroblasts during serum starvation (57), whereas VEGF protects HepG2 and endothelial cells against apoptosis induced by TNF-␣ or serum deprivation (25,58). Furthermore, chronic hypoxia in the lung not only protects smooth muscle cells from apoptosis but can even stimulate these cells to replicate possibly via induction by PDGF-B and endothelin-1, which are secreted by endothelial cells (59,60).…”