Cyclin-mediated G1 arrest by celecoxib differs in low-versus high-grade bladder cancer.
BACKGROUND
Celecoxib and other non-steroidal anti-inflammatory drugs (NSAIDs) are being evaluated in the prevention of bladder and other cancers. Here we investigate molecular effects of celecoxib independent of cyclooxygenase (COX)-2 expression levels in urothelial carcinoma of the bladder.


METHODS
Low-grade RT-4 and high-grade UM-UC-3 bladder cancer cells were treated with 0-50 muM celecoxib. Growth, cell cycle and apoptosis were measured by crystal violet elution and flow cytometry. Western analysis was performed for COX-2, Rb, cyclin B1/D1, and phospho-cyclin B1/D1. COX-2 induction was achieved with phorbol ester.


RESULTS
Celecoxib inhibited growth of RT-4 and UM-UC-3, with G(1) cell cycle arrest and altered cyclin B1/D1 expression in RT-4, whereas Rb up-regulation occurred in UM-UC-3. Apoptosis occurred in both cell lines.


CONCLUSIONS
Celecoxib induces G(1) cell cycle arrest in low- and high-grade bladder cancer by different pathways. This heterogeneous molecular response supports combination approaches to prevention and treatment.
Department of Urology, William S. Middleton Memorial Veterans Hospital, and Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. Gee@urology.wisc.edu
Jason R
JR
Gee
Corrie B
CB
Burmeister
Thomas C
TC
Havighurst
Kyungmann
K
Kim
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D000068579:Celecoxib; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D056744:Cyclin B1 / Q000096:biosynthesis*; D019938:Cyclin D1 / Q000096:biosynthesis*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D011720:Pyrazoles / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D013449:Sulfonamides / Q000494:pharmacology*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; C534699:CCNB1 protein, human; C530104:CCND1 protein, human; D056744:Cyclin B1; D011720:Pyrazoles; D016160:Retinoblastoma Protein; D013449:Sulfonamides; D019938:Cyclin D1; D051546:Cyclooxygenase 2; D000068579:Celecoxib