Abstract
Transcription factor c-Myb is required for maintenance of progenitor cells in colon epithelium. Deregulation of c-Myb is frequently linked with tumorigenesis. For colorectal carcinomas, high c-Myb expression denotes tumors with poor prognosis. Oxidative stress is closely related to all aspects of cancer, including resistance of tumors to anticancer treatment. Evasion of apoptosis induced by chemotherapeutics is one of the mechanisms by which reactive oxygen species (ROS) exert their tumor-promoting effects. Identification of novel biomarkers predicting the clinical response to pro-oxidant therapies is essential for personalized cancer therapies. We followed molecular mechanisms of the c-Myb-induced chemoresistance of colorectal cancer cells. Cells overexpressing c-Myb displayed higher viability and produced significantly more ROS upon treatment with cisplatin and doxorubicin. We also found the c-Myb-induced upregulation of phospho-MAPKp38. This kinase acts as a key sensor of oxidative stress. Using a panel of p38 inhibitors we identified the MAPKp388 isoform as a key molecule mediating c-Myb-induced chemoresistance. In summary, we discovered a novel function of the c-Myb-p38 signaling in the oxidative stress response induced in colon cancers cells by standard chemotherapeutics. (Supported by grant NT13441/2012 of the Internal Grant Agency of the Ministry of Health, Czech Republic.)
Published Version
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