Maintenance of higher H2O2 levels, and its mechanism of action to induce growth in breast cancer cells: Important roles of bioactive catalase and PP2A

• Published in: Free radical biology & medicine Vol. 53; no. 8; pp. 1541 - 1551
• Main Authors: Sen, Suvajit, Kawahara, Brian, Chaudhuri, Gautam
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.10.2012
• Subjects: Apoptosis; bioactive properties; Blotting, Western; Breast - cytology; Breast - metabolism; Breast cancer; breast neoplasms; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Catalase; Catalase - antagonists & inhibitors; Catalase - genetics; Catalase - metabolism; Cell Cycle; Cell Proliferation; Cells, Cultured; Colony-Forming Units Assay; Female; Flow Cytometry; genes; glutathione peroxidase; Growth; Humans; hydrogen peroxide; Hydrogen Peroxide - metabolism; mechanism of action; mitogen-activated protein kinase; Oxidative Stress; Phosphorylation; PP2A; Protein Phosphatase 2 - metabolism; RNA, Small Interfering - genetics; Superoxide; superoxide anion; superoxide dismutase; Superoxides - metabolism; transfection; Superoxide; PP2A; Breast cancer; Catalase; Growth; Apoptosis
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2012.06.030

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. ► Superoxide down regulates catalase activity in breast cancer cells. ► Down regulation of catalase increases H2O2 levels. ► Increased H2O2 levels elicit increase in proliferation by inactivating PP2A.