Resistance of colon cancer cells to long‐term 5‐fluorouracil exposure is correlated to the relative level of Bcl‐2 and Bcl‐XL in addition to Bax and p53 status

Abstract

Defects in apoptosis have been implicated in chemoresistance of colon cancer cells. We report here the ability to resist to 5‐fluorouracil‐induced apoptosis of 8 colon cancer cell lines differing in p53 and bax status: p53^−/0bax^+/+ for TC7, SW480, HT‐29; p53^+/+bax^−/− for LS174T, LoVo; p53^+/+ bax^+/− for HCT116; p53^+/+ or p53^+/0bax^+/+ for LS513 or HCT‐EB, respectively. To approximate to the in vivo therapy, the cell lines were exposed to a long‐term treatment of 5‐FU. The analysis of proteins implicated in the apoptotic pathway has shown that the independent analysis of p53 or bax status was not sufficient to predict the extent of drug‐resistance of all cell lines. In p53^+/+ cell lines but not in p53^−/0 cell lines, a low level of the pro‐apoptotic Bax protein was correlated with a greater resistance of cells to 5‐FU. In addition, we found that high levels of anti‐apoptotic Bcl‐2 and Bcl‐x_L proteins combined with a low level of Bax were correlated to high 5‐FU resistance of wild‐type p53 cell lines. The same correlation was obtained for 2 out of 3 mutated p53 cell lines. In conclusion, the relative levels of Bcl‐2, Bcl‐x_L and Bax may altogether contribute to determine the resistance of a majority of colon tumor cells to long‐term 5‐FU treatment, whatever their p53 status.