BH3 profiling discriminates the anti‑apoptotic status of 5‑fluorouracil‑resistant colon cancer cells

5Fluorouracil (5FU) is a cytotoxic anticancer drug commonly used for patients with advanced colon cancer. This drug effectively reduces the size of tumors to a certain degree; however, cancer cells can gradually acquire resistance, resulting in disease progression. To identify the mechanism of 5FU resistance, we established three 5FUresistant colon cancer cell lines and analyzed both apoptosisrelated protein expression levels and BH3 profiling. These 5FUresistant colon cancer cell lines acquired apoptotic resistance to 5FU. Although apoptosisrelated protein expression levels were altered in each 5FUresistant colon cancer cell line variably, BH3 profiling indicated BCLXL dependence in 5FUresistant HT29 cells only. Functional BCLXL inhibition in 5FUresistant HT29 cells not only sensitized the cells to apoptosis but also overcame 5FU resistance. The apoptotic BIM protein was preferentially sequestered, thereby resulting in acquired dependence on BCLXL for survival. Additionally, in vivo models showed that BCLXL inhibition controlled tumor progression. These results indicate that BH3 profiling facilitates the identification of the functional role of antiapoptotic proteins during drug resistance and has clinical implications for colon cancer in targeting specific proteins such as BCLXL.