PI3K and ERK-Induced Rac1 Activation Mediates Hypoxia-Induced HIF-1α Expression in MCF-7 Breast Cancer Cells
Open Access
- 27 September 2011
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 6 (9), e25213
- https://doi.org/10.1371/journal.pone.0025213
Abstract
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. 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. 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.Keywords
This publication has 60 references indexed in Scilit:
- Role of ROS in ischemia-induced lung angiogenesisAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2010
- HER2/ErbB2-induced Breast Cancer Cell Migration and Invasion Require p120 Catenin Activation of Rac1 and Cdc42Online Journal of Public Health Informatics, 2010
- ERK activation of p21 activated kinase-1 (Pak1) is critical for medulloblastoma cell migrationClinical & Experimental Metastasis, 2010
- Hypoxia Increases ROS Signaling and Cytosolic Ca2+ in Pulmonary Artery Smooth Muscle Cells of Mouse Lungs SlicesAntioxidants and Redox Signaling, 2010
- Reactive Oxygen Species-generating Mitochondrial DNA Mutation Up-regulates Hypoxia-inducible Factor-1α Gene Transcription via Phosphatidylinositol 3-Kinase-Akt/Protein Kinase C/Histone Deacetylase PathwayOnline Journal of Public Health Informatics, 2009
- Rac1 Signaling Modulates BCL-6-Mediated Repression of Gene TranscriptionMolecular and Cellular Biology, 2009
- Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt–β-catenin and Wnt–RhoA–Rac1 pathwaysThe Journal of cell biology, 2009
- Hypoxia activates NADPH oxidase to increase [ROS]i and [Ca2+]i through the mitochondrial ROS-PKCɛ signaling axis in pulmonary artery smooth muscle cellsFree Radical Biology & Medicine, 2008
- Hypoxia-induced IL-18 Increases Hypoxia-inducible Factor-1α Expression through a Rac1-dependent NF-κB PathwayMolecular Biology of the Cell, 2008
- Hypoxia — a key regulatory factor in tumour growthNature Reviews Cancer, 2002