Resistance of colon cancer cells to long-term 5-fluorouracil exposure is correlated to the relative level of Bcl-2 and Bcl-X(L) in addition to Bax and p53 status.
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(-/0)bax(+/+) for TC7, SW480, HT-29; p53(+/+)bax(-/-) for LS174T, LoVo; p53(+/+) bax(+/-) for HCT116; p53(+/+) or p53(+/0)bax(+/+) 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.
Violette
Sabine
S
INSERM U505, Université Pierre et Marie Curie, Paris, France.
Poulain
Laurent
L
Dussaulx
Elisabeth
E
Pepin
Dominique
D
Faussat
Anne-Marie
AM
Chambaz
Jean
J
Lacorte
Jean-Marc
JM
Staedel
Cathy
C
Lesuffleur
Thécla
T
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D015153:Blotting, Western; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology*; D005838:Genotype; D019073:HT29 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009154:Mutation; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D000964:Antimetabolites, Antineoplastic; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D005472:Fluorouracil