Hypoxia-Inducible Factor 1α Determines Gastric Cancer Chemosensitivity via Modulation of p53 and NF-κB
Figure 6
ROS as molecular mediator of the HIF-1α effect on chemosensitivity in AGS KD cells.
(A–D) AGS KD cells were pretreated for 16 h with different concentrations of the NADPH oxidase inhibitors diphenyleneiodonium (DPI) or apocynin. Proliferation of DPI-pretreated (A) or apocynin-pretreated (B) AGS KD cells 24 h after treatment with 10 µg/ml 5-FU under normoxic conditions (***, P<0.001). Cell numbers are shown as percent of untreated cells. (C and D) The effect of DPI (C) and apocynin (D) on p53 and p21 protein levels was determined by immunoblot analysis using whole cell extracts of AGS KD cells treated for 24 h with 10 µg/ml 5-FU. (E) Proposed model for HIF-1-dependent regulation of chemosensitivity by ROS-induced modulation of p53. (left panel) Chemotherapy-induced response in HIF-1-competent cells. HIF-1 counteracts generation of ROS at the mitochondrial level. Decreased ROS levels in turn abate activation of p53 and allow for cell cycle progression despite chemotherapy. Hence, HIF-1-competent cells display a more chemoresistant phenotype. Ub, ubiquitin; P, phosphate. (right panel) Chemotherapy-induced response in HIF-1-deficient cells. Inactivation of HIF-1 leads to accelerated mitochondrial ROS generation. ROS are potent inducers of p53 and thus boost activation of p53 by chemotherapeutic agents. P53 in turn transactivates -among others - the cyclin-dependent kinase (CDK) inhibitor p21 and inhibits NF-κB activity. The combined activation of p53 and inhibition of NF-κB, result in apoptosis and/or senescence of HIF-1-deficient cells, hence a more chemosensitive phenotype.
