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REACTIVE OXYGEN SPECIES REGULATE HYPOXIA‐INDUCIBLE FACTOR 1 AND VASCULAR ENDOTHELIAL GROWTH FACTOR EXPRESSION
Author(s) -
Chen Yi C,
Xia Chang,
Jiang BingHua
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a218-c
Subject(s) - vascular endothelial growth factor , angiogenesis , reactive oxygen species , hypoxia inducible factors , vascular endothelial growth factor a , microbiology and biotechnology , protein kinase b , cancer research , pi3k/akt/mtor pathway , cell growth , signal transduction , biology , chemistry , vegf receptors , biochemistry , gene
Ovarian cancer is the leading cause of death for women in Western countries. Hypoxia‐inducible factor 1 (HIF‐1) and vascular endothelial growth factor (VEGF) are important proteins involved in angiogenesis and tumor formation. HIF‐1 activates the expression of VEGF. Reactive oxygen species (ROS) including H 2 O 2 , O 2 .‐ and OH. are generated by cellular aerobic metabolism and are induced by heavy metals, growth factors, and cytokine. Recent studies indicated that ROS are involved in the development and growth of human cancers. In this study, we studied the effects of ROS in regulating HIF‐1 and VEGF expression in ovarian cancer cells. Our studies showed that ovarian cancer cells OVCAR‐3 and A2780/CP70 produced high levels of ROS than immortalized ovarian surface epithelium (IOSE) cells. We found the addition of low concentrations of H 2 O 2 and O 2 .‐ stimulated ovarian cancer cell proliferation and HIF 1α expression in dose‐ and time‐dependent manner. Inhibition of endogenous ROS by DPI and rotenone greatly decreased cell proliferation and HIF‐1α and VEGF expression. By using luciferase reporter assay, we demonstrated that VEGF was induced by ROS at transcriptional level via induction of HIF‐1α expression. To study the signaling pathways involved in ROS‐induced HIF1α expression, we found that PI3K/AKT, and MAPK signaling pathways are downstream of ROS to regulate VEGF and HIF‐1α expression in the cells. This work was supported by American Cancer Society Research Scholar Grant 04‐076‐01‐TBE, and by grant P20 RR16477 from the National Center for Research Resources awarded to the West Virginia IDeA Network for Biomedical Research Excellence.