Abstract
BackgroundHypoxia-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.Methodology/Principal FindingsIn 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/SignificanceTaken 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.
Highlights
Angiogenesis is a relatively early event in the progression of human cancer
We found that the vascular endothelial growth factor (VEGF) mRNA transcript levels were significantly increased in MCF-7 cells under hypoxia (Fig. 1B)
These results indicate that hypoxia can stimulate reactive oxygen species (ROS) generation in breast cancer cells, which acts as the upstream effector of PI3K and extracellular signal-regulated kinase (ERK) in mediating Rac1 activation and HIF-1a expression in hypoxic MCF-7 cells
Summary
Angiogenesis is a relatively early event in the progression of human cancer. A characteristic feature of many human malignancies [7,8], can stimulate the expression of numerous angiogenic factors by the induction of hypoxia-inducible factor-1 (HIF-1), which is a heterodimeric protein composed of HIF-1a and HIF-1b subunits. Hypoxia inhibits HIF-1a hydroxylation and allows its translocation to the nucleus, where it binds to HIF-1b to form an active complex and initiates the transcription of VEGF and other angiogenic factors [9,10,11]. The role of HIF-1a in angiogenesis has been reported, the upstream signaling events stimulating HIF-1a expression activated by hypoxia are still not well characterized. Hypoxia-inducible factor 1 (HIF-1a) expression induced by hypoxia plays a critical role in promoting tumor angiogenesis and metastasis. The molecular mechanisms underlying the induction of HIF-1a in tumor cells remain unknown
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