Celecoxib induces anoikis in human colon carcinoma cells associated with the deregulation of focal adhesions and nuclear translocation of p130Cas.
Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is effective as chemopreventive against colon cancer and it is the only nonsteoroidal antiinflammatory drug approved by the FDA for adjuvant therapy in patients with familial adenomatous polyposis. It is also being evaluated, within Phase II and III clinical trials, in combination with standard chemotherapy to treat sporadic colorectal cancer. Nevertheless, its antitumor mechanism of action is still not fully understood. In this study, we have evaluated the in vitro growth inhibitory effect of celecoxib in colon carcinoma cells and analyzed its mechanism of action. We report that the deregulation of the focal adhesion assembly protein Crk-associated substrate 130 kDa (p130Cas) by celecoxib plays a relevant role in the cytotoxic effect of this drug. Thus, celecoxib induces the proteolysis of p130Cas and the nuclear translocation of the 31 kDa generated fragment leading to apoptosis. Furthermore, overexpression of wild-type p130Cas reverts, in part, the growth inhibitory effect of celecoxib. In contrast, FAK and AKT do not appear to be involved in this activity. Our data suggest, for the first time, that the antitumor mechanism of action of celecoxib includes the induction of anoikis, an effect that is not related to COX-2 inhibition. Besides providing new insights into the antitumor effect of celecoxib, this novel mechanism of action holds potential relevance in drug development. Indeed, our results open the possibility to develop new celecoxib derivatives that induce anoikis without COX-2 inhibition so as to avoid the cardiovascular toxicity recently described for the COX-2 inhibitors.
Casanova
Isolda
I
Laboratori d'Investigació Gastrointestinal de l'Institut de Recerca of the Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Parreño
Matilde
M
Farré
Lourdes
L
Guerrero
Sílvia
S
Céspedes
M Virtudes
MV
Pavon
Miguel Angel
MA
Sancho
Francesc J
FJ
Marcuello
Eugenio
E
Trias
Manuel
M
Mangues
Ramon
R
D023102:Anoikis / Q000187:drug effects*; D002277:Carcinoma / Q000473:pathology*; D000068579:Celecoxib; D002467:Cell Nucleus / Q000737:chemistry; D003110:Colonic Neoplasms / Q000473:pathology*; D050719:Crk-Associated Substrate Protein / Q000378:metabolism* / Q000493:pharmacokinetics; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D022001:Focal Adhesions / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
D050719:Crk-Associated Substrate Protein; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib