Faculty Collaboration Database

Celecoxib toxicity is cell cycle phase specific. Cancer Res 2007 Apr 15;67(8):3801-8

Date

04/19/2007

Pubmed ID

17440094

DOI

10.1158/0008-5472.CAN-06-3780

Scopus ID

2-s2.0-34248584884 (requires institutional sign-in at Scopus site)   38 Citations

Abstract

Celecoxib inhibits proliferation and induces apoptosis in human tumors, but the molecular mechanisms for these processes are poorly understood. In this study, we evaluated the ability of celecoxib to induce toxicity in head and neck squamous cell carcinomas (HNSCC) and explored the relationships between celecoxib-induced cell cycle inhibition and toxicity in HNSCC. Celecoxib inhibited the proliferation of UM-SCC-1 and UM-SCC-17B cells both in vitro and in vivo, accompanied by G(1) phase cell cycle arrest and apoptosis. Celecoxib induced p21(waf1/cip1) at the transcriptional level independent of wild-type p53 function, leading to decreased expression of cyclin D1 and hypophosphorylation of Rb, with subsequent marked downstream decreases in nuclear E2F-1 protein expression and E2F transactivating activity by luciferase reporter assay. Cell cycle phase-specific cytometric sorting showed that celecoxib induced clonogenic toxicity preferentially to cells within the S phase greater than G(1) and G(2) phases. Levels of p21(waf1/cip1) and cyclin D1 protein were reduced in the S phase compared with the G(1) and G(2) phases, suggesting a possible protective role for p21(waf1/cip1) expression in celecoxib toxicity. In conclusion, we show that celecoxib has marked antiproliferative activity against head and neck cancer cells through transcriptional induction of p21(waf1/cip1) and G(1) phase accumulation leading to S phase-specific clonogenic toxicity. We additionally show that a profound inhibition of nuclear E2F function provides a possible mechanism for this S phase-specific toxicity.

Author List

Bock JM, Menon SG, Sinclair LL, Bedford NS, Goswami PC, Domann FE, Trask DK

Author

Jonathan Bock MD Professor in the Otolaryngology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Carcinoma, Squamous Cell
Celecoxib
Cell Growth Processes
Cyclin-Dependent Kinase Inhibitor p21
E2F Transcription Factors
Female
G1 Phase
Head and Neck Neoplasms
Humans
Mice
Mice, Nude
Pyrazoles
RNA, Messenger
S Phase
Sulfonamides
Transcriptional Activation