c-Myb prevents apoptosis of colon carcinoma cells: modulating effects of cyclooxygenase 2?
|Fakulta / Pracoviště MU|
|Popis||Colon carcinoma belongs to the most frequent tumor diseases in industrial countries. Development of the colon tumors is associated with mutations in various protooncogenes and tumor suppressor genes of colon cells. The c-myb protooncogene codes for transcription factor that is involved in colorectal cancerogenesis. c-myb expression is frequently up-regulated in colon carcinomas compared to non-malignant colonic mucosa. The set of the Myb-targeted genes includes the cox-2 gene coding for cyclooxygenase-2. The Cox-2-specific inhibitors are promising tools of anti-cancer therapies. The aim of this study is to clarify the role of c-Myb and Cox-2 cooperation in regulation of apoptosis of colon carcinoma cell lines HCT116 and HT-29. We prepared HCT116 cells overexpressing c-Myb and HT-29 cells with silenced c-myb expression and confirmed that up- and down-regulation of c-Myb correlate with expression of cox-2. HCT116 cells overexpressing cox-2 and HT-29 cells with silenced cox-2 expression were derived as well. We studied the role of c-Myb/Cox-2 in regulation of apoptosis in response to cis-platin and TRAIL. We showed that overexpression of c-myb stimulates resistance, while silencing of c-myb stimulates sensitivity of the colon carcinoma cells to both cis-platin and TRAIL. On the other hand our findings revealed somewhat controversial function of Cox-2 in apoptosis. TRAIL-induced extrinsic apoptotic pathway seems to be unaffected by overexpression/silencing or pharmacological inhibition of Cox-2. On the other hand Cox-2 overexpression/silencing modulates CDDP-induced intrinsic (mitochondrial) apoptotic pathway in a different way than Cox-2 inhibitor NS-398. We conclude that c-Myb suppresses cis-platin- and TRAIL-induced apoptosis of colon carcinoma cells independently on activity of Cox-2.|