TY - JOUR
T1 - Ibuprofen inhibits colitis-induced overexpression of tumor- related Rac1b
AU - Matos, Paulo
AU - Kotelevets, Larissa
AU - Gonçalves, Vânia
AU - Henriques, Andreia
AU - Zerbib, Philippe
AU - Moyer, Mary Pat
AU - Chastre, Eric
AU - Jordan, Peter
N1 - Funding Information:
Address all correspondence to: Dr Peter Jordan, Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal. E-mail: [email protected] 1This work was supported by the Fundação Calouste Gulbenkian (grant 96495) and Fundação para a Ciência e Tecnologia, Portugal (grant PEst-OE/BIA/UI4046/2011 to the BioFIG Research Unit and contract Ciência2007 to P.M.). Competing interests: None. 2These authors contributed equally to this work. Received 9 November 2012; Revised 27 November 2012; Accepted 29 November 2012 Copyright © 2013 Neoplasia Press, Inc. All rights reserved 1522-8002/13/$25.00 DOI 10.1593/neo.121890
PY - 2013/1
Y1 - 2013/1
N2 - 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.
AB - 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.
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U2 - 10.1593/neo.121890
DO - 10.1593/neo.121890
M3 - Article
C2 - 23359345
AN - SCOPUS:84873020742
SN - 1522-8002
VL - 15
SP - 102
EP - 111
JO - Neoplasia (United States)
JF - Neoplasia (United States)
IS - 1
ER -