title: Maintenance of higher H₂O₂ levels, and its mechanism of action to induce growth in breast cancer cells: important roles of bioactive catalase and PP2A.
abstract: We assessed the catalase bioactivity and hydrogen peroxide (H₂O₂) production rate in human breast cancer (HBC) cell lines and compared these with normal human breast epithelial (HBE) cells. We observed that the bioactivity of catalase was decreased in HBC cells when compared with HBE cells. This was also accompanied by an increase in H₂O₂ steady-state levels in HBC cells. Silencing the catalase gene led to a further increase in the steady-state level of H₂O₂ which was also accompanied by an increase in growth rate of HBC cells. Catalase activity was up regulated on treatment with superoxide (O₂⁻) scavengers such as pegylated SOD (PEG-SOD, indicating inhibition of catalase by the increased O₂⁻ produced by HBC cells. Transfection of either catalase or glutathione peroxidase to HBC cells decreased intracellular H₂O₂ levels and led to apoptosis of these cells. The H₂O₂ produced by HBC cells inhibited PP2A activity accompanied by increased phosphorylation of Akt and ERK1/2. The importance of catalase bioactivity in breast cancer was further confirmed as its bioactivity was also decreased in human breast cancer tissues when compared to normal breast tissues. We conclude that inhibition of catalase bioactivity by O₂⁻ leads to an increase in steady-state levels of H₂O₂ in HBC cells, which in turn inhibits PP2A activity, leading to phosphorylation of ERK 1/2 and Akt and resulting in HBC cell proliferation.
authors: Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095-6928, USA. ssen@mednet.ucla.edu
authors: Suvajit
authors: S
authors: Sen
authors: Brian
authors: B
authors: Kawahara
authors: Gautam
authors: G
authors: Chaudhuri
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D001940:Breast / Q000166:cytology* / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002374:Catalase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D013481:Superoxides / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D013481:Superoxides; D006861:Hydrogen Peroxide; D002374:Catalase; D054648:Protein Phosphatase 2