Reactive oxygen species regulate epidermal growth factor-induced vascular endothelial growth factor and hypoxia-inducible factor-1α expression through activation of AKT and P70S6K1 in human ovarian cancer cells

Ling Zhi Liu, Xiao Wen Hu, Chang Xia, Jie He, Qiong Zhou, Xianglin Shi, Jing Fang, Bing Hua Jiang

Research output: Contribution to journalArticlepeer-review

181 Scopus citations

Abstract

The epidermal growth factor (EGF) and EGF receptor (EGFR) family are often overexpressed in various human cancers including ovarian cancer. While it is generally believed that reactive oxygen species (ROS) are involved in the intracellular signaling events, the role of ROS in EGF-induced angiogenesis and carcinogenesis remains to be elucidated. The present study investigated the role of ROS in the regulation of AKT, p70S6K1, vascular endothelial growth factor (VEGF), and hypoxia-inducible factor 1 (HIF-1) in ovarian cancer cells. In this study, OVCAR-3 cells were treated with EGF and catalase, an H2O2 scavenger. EGF treatment increases H2O2 production, leading to activation of the AKT/p70S6K1 pathway, resulting in increased VEGF expression at the transcriptional level. The inhibition of H2O2 production by catalase abolished EGF-induced AKT and p70S6K1 activation, and VEGF expression through HIF-1α expression. Forced expression of p70S6K1 and HIF-1α reversed catalase- and rapamycin-inhibited VEGF transcriptional activation. We also showed that rapamycin, p70S6K1 inhibitor and catalase overexpression inhibited tumor angiogenesis. This study demonstrates a novel mechanism of EGF-induced VEGF and HIF-1α expression through production of H2O2 and activation of AKT and p70S6K1 in human ovarian cancer cells. This study also indicates that p70S6K1 and H2O2 are important in tumor angiogenesis. The results of the study could have an important implication in ovarian cancer therapy.

Original languageEnglish
Pages (from-to)1521-1533
Number of pages13
JournalFree Radical Biology and Medicine
Volume41
Issue number10
DOIs
StatePublished - Nov 15 2006

Bibliographical note

Funding Information:
This work was supported by National Natural Science Foundation of China Grants 30470361 and 30570962. L.Z. Liu is supported by China Postdoctoral Science Foundation and Shanghai Postdoctoral Science Foundation. The authors thank Ms Bei-bei Fu for assistance in cell culture, and Dr. John Blenis for providing p70S6K1 construct.

Keywords

  • AKT
  • Epidermal growth factor (EGF)
  • Hypoxia-inducible factor-1 (HIF-1)
  • Reactive oxygen species (ROS)
  • Vascular endothelial growth factor (VEGF)
  • p70S6K1

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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