Journal
PLOS ONE
Volume 6, Issue 9, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0025213
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Funding
- National Natural Science Foundation of China [30872926]
- Program for Advanced Talents within Six Industries of Jiangsu Province [08-D]
- Postdoctoral Science Foundation of Jiangsu Province
- Science Development Foundation of Nanjing Medical University [2010NJMUZ35]
- School of Basic Medical Sciences, Nanjing Medical University
- State Key Laboratory of Reproductive Medicine, China
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Background: Hypoxia-inducible factor 1 (HIF-1 alpha) expression induced by hypoxia plays a critical role in promoting tumor angiogenesis and metastasis. However, the molecular mechanisms underlying the induction of HIF-1 alpha in tumor cells remain unknown. Methodology/Principal Findings: In this study, we reported that hypoxia could induce HIF-1 alpha and VEGF expression accompanied by Rac1 activation in MCF-7 breast cancer cells. Blockade of Rac1 activation with ectopic expression of an inactive mutant form of Rac1 (T17N) or Rac1 siRNA downregulated hypoxia-induced HIF-1 alpha and VEGF expression. Furthermore, Hypoxia increased PI3K and ERK signaling activity. Both PI3K inhibitor LY294002 and ERK inhibitor U0126 suppressed hypoxia-induced Rac1 activation as well as HIF-1 alpha expression. Moreover, hypoxia treatment resulted in a remarkable production of reactive oxygen species (ROS). N-acetyl-L-cysteine, a scavenger of ROS, inhibited hypoxia-induced ROS generation, PI3K, ERK and Rac1 activation as well as HIF-1 alpha expression. Conclusions/Significance: Taken together, our study demonstrated that hypoxia-induced HIF-1 alpha expression involves a cascade of signaling events including ROS generation, activation of PI3K and ERK signaling, and subsequent activation of Rac1.
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