title: PI3K and ERK-induced Rac1 activation mediates hypoxia-induced HIF-1α expression in MCF-7 breast cancer cells.
abstract: BACKGROUND
  Hypoxia-inducible factor 1 (HIF-1α) expression induced by hypoxia plays a critical role in promoting tumor angiogenesis and metastasis. However, the molecular mechanisms underlying the induction of HIF-1α in tumor cells remain unknown.
  
  
  RESULTS
  In this study, we reported that hypoxia could induce HIF-1α 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-1α 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-1α 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-1α expression.
  
  
  CONCLUSIONS
  Taken together, our study demonstrated that hypoxia-induced HIF-1α expression involves a cascade of signaling events including ROS generation, activation of PI3K and ERK signaling, and subsequent activation of Rac1.
authors: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
authors: Jun
authors: J
authors: Du
authors: Rui
authors: R
authors: Xu
authors: Zhenzhen
authors: Z
authors: Hu
authors: Yinhui
authors: Y
authors: Tian
authors: Yichao
authors: Y
authors: Zhu
authors: Luo
authors: L
authors: Gu
authors: Lei
authors: L
authors: Zhou
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D002070:Butadienes / Q000494:pharmacology; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D002070:Butadienes; D002867:Chromones; D048049:Extracellular Signal-Regulated MAP Kinases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009025:Morpholines; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017382:Reactive Oxygen Species; D020830:rac1 GTP-Binding Protein; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one