Ibuprofen inhibits colitis-induced overexpression of tumor-related Rac1b.
The serrated pathway to colorectal tumor formation involves oncogenic mutations in the BRAF gene, which are sufficient for initiation of hyperplastic growth but not for tumor progression. A previous analysis of colorectal tumors revealed that overexpression of splice variant Rac1b occurs in around 80% of tumors with mutant BRAF and both events proved to cooperate in tumor cell survival. Here, we provide evidence for increased expression of Rac1b in patients with inflamed human colonic mucosa as well as following experimentally induced colitis in mice. The increase of Rac1b in the mouse model was specifically prevented by the nonsteroidal anti-inflammatory drug ibuprofen, which also inhibited Rac1b expression in cultured HT29 colorectal tumor cells through a cyclooxygenase inhibition.independent mechanism. Accordingly, the presence of ibuprofen led to a reduction of HT29 cell survival in vitro and inhibited Rac1b-dependent tumor growth of HT29 xenografts. Together, our results suggest that stromal cues, namely, inflammation, can trigger changes in Rac1b expression in the colon and identify ibuprofen as a highly specific and efficient inhibitor of Rac1b overexpression in colorectal tumors. Our data suggest that the use of ibuprofen may be beneficial in the treatment of patients with serrated colorectal tumors or with inflammatory colon syndromes.
Department of Human Genetics, National Health Institute Doutor Ricardo Jorge, Lisbon, Portugal.
Paulo
P
Matos
Larissa
L
Kotelevets
Vania
V
Goncalves
Andreai F A
AF
Henriques
Andreia
A
Henriques
Philippe
P
Zerbib
Mary Pat
MP
Moyer
Eric
E
Chastre
Peter
P
Jordan
D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D003092:Colitis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
D011451:Prostaglandin-Endoperoxide Synthases; D048493:Proto-Oncogene Proteins B-raf; D020830:rac1 GTP-Binding Protein; D007052:Ibuprofen