Celecoxib toxicity is cell cycle phase specific

被引:32
作者
Bock, Jonathan M.
Menon, Sarita G.
Sinclair, Lori L.
Bedford, Nichole S.
Goswami, Prahhat C.
Domann, Frederick E.
Trask, Douglas K.
机构
[1] Univ Iowa, Hosp & Clin, Dept Otolaryngol Head & Neck Surg, Iowa City, IA 52242 USA
[2] Univ Iowa, Hosp & Clin, Dept Radiat Oncol, Iowa City, IA 52242 USA
关键词
D O I
10.1158/0008-5472.CAN-06-3780
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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, 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, and G(2) phases. Levels of p21(waf1/cpi1) and cyclin D1 protein were reduced in the S phase compared with the G, and G2 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, 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.
引用
收藏
页码:3801 / 3808
页数:8
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