The Study On5-Fu Sensitivity In Colon Cancer Cells Regulated By C-Myc Under Hypoxic Microenvironment

Colon cancer is the most common malignant tumor in the Western Europe, North America and other developed countries and also one of the common malignant tumors in China. In the past3decades, there is a rising incidence of colon cancer in most countries or regions, including China.5-fluorouracil based chemotherapy effectively decrease the mortality rate of patients with colon cancer, but the subsequent5-fluorouracil drug sensitivity to colon cancer chemotherapy has brought new challenges and difficulties. In addition, it will develop in a hypoxic condition with the rapid increasing size of colon cancer. This hypoxic microenvironment will decrease the sensitivity of chemotherapy. Our previous study found that the expression of c-Myc in colon cancer cells, being regulated by hypoxic inducible factors and ubiquitinoylation, was reduced in a stepwise manner under hypoxic stress. This indicates that the expression level of c-Myc is likely to be related to the drug sensitivity in tumors.In this study, modern technologies in cellular and molecular biology were applied to clarify the phenomenon of impaired chemotherapeutic sensitivity for5-fluorouracil under hypoxic microenvironment. c-Myc overexpressed colon cancer cell lines were established to elucidate the relationship between the expression of c-Myc and5-fluorouracil sensitivity. Materials and methods:1. Relative cell viabilities of colon cancer cells treated by5-fluorouracil at different gradient concentrations under nomoxic and hypoxic environment were measured by MTS to calculate the IC50of5-fluorouracil. The sensitivities of5-fluorouracil on colon cancer cells under nomoxia and hypoxia were evaluated.2. RKO cells were stably transfected with c-myc or incubated with ubiquitination inhibitor MG132. Cytotoxic effect of5-Fu on RKO cells under chronic hypoxic microenvironment was observed.Results:1. IC50of5-Fu on colon cancer cells (including HT29, HCT116, SW480and SW620, RKO, Lovo) was increased under hypoxic condition (1%O2).2. c-Myc was overexpressed after stable transfection of c-Myc plasmid in RKO cells, accompanied by improvement of5-Fu sensitivity. The expression level of c-Myc was related to the sensitivity of5-Fu.3. c-Myc was upregulated after the treatment of0.1uM MG132. The administration of MG132in RKO cells enhances the sensitivity of5-Fu under hypoxia.Conclusion:1. Under the condition of hypoxia (1%O2), the sensitivity of colon cancer cells (including HT29, HCT116, SW480and SW620, RKO, Lovo) to5-Fu were impaired.2. The expression level of c-Myc was related to the drug sensitivity to5-Fu chemotherapy under hypoxic condition. Ectopic expression of c-Myc or combined with MG132could increase the sensitivity of5-Fu.