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Open Access Research article

Cyclooxygenase 2-dependent and independent activation of Akt through casein kinase 2α contributes to human bladder cancer cell survival

Keiji Shimada1*, Satoshi Anai2, Develasco A Marco3, Kiyohide Fujimoto2 and Noboru Konishi1

Author Affiliations

1 Department of Pathology, Nara Medical University School of Medicine, Shijo-cho 840, Kashihara city, Nara, 634-8521; Japan

2 Department of Urology, Nara Medical University School of Medicine, Shijo-cho 840, Kashihara city, Nara, 634-8521; Japan

3 Department of Urology, Kinki University School of Medicine, Sayama city, Osaka, 589-8511, Japan

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BMC Urology 2011, 11:8  doi:10.1186/1471-2490-11-8

Published: 18 May 2011

Abstract

Background

Survival rate for patients presenting muscle invasive bladder cancer is very low, and useful therapeutic target has not been identified yet. In the present study, new COX2 downstream signals involved in urothelial carcinoma cell survival were investigated in vitro and in vivo.

Methods

COX2 gene was silenced by siRNA transfection. Orthotopic implantation animal model and transurethral instillation of siRNA with atelocollagen was constructed to examine the effects of COX2 knockdown in vivo. Cell cycle was examined by flowcytoketry. Surgical specimens derived from patients with urinary bladder cancer (all were initially diagnosed cases) were used for immunohistochemical analysis of the indicated protein expression in urothelial carcinoma cells.

Results

Treatment with the COX2 inhibitor or knockdown of COX2 reduced expression of casein kinase (CK) 2 α, a phophorylated Akt and urokinase type plasminogen activator (uPA), resulting in p27 induction, cell cycle arrest at G1 phase and cell growth suppression in human urothelial carcinoma cell lines expressing COX2. Silencing of CK2α exhibited the similar effects. Even in UMUC3 cells lacking the COX2 gene, COX2 inhibition also inhibited cell growth through down-regulation of the CK2α-Akt/uPA axis. The mouse orthotropic bladder cancer model demonstrated that the COX2 inhibitor, meloxicam significantly reduced CK2α, phosphorylated Akt and uPA expression, whereas induced p27 by which growth and invasiveness of bladder cancer cells were strongly inhibited. Immunohistochemically, high expression of COX2, CK2α and phosphorylated form of Akt was found in high-grade, invasive carcinomas as well as carcinoma in situ, but not in low-grade and noninvasive phenotypes.

Conclusions

COX2-dependent and independent activation of CK2α-Akt/uPA signal is mainly involved in urothelial carcinoma cell survival, moreover, not only COX2 but also CK2α could be direct targets of COX2 inhibitors.

Keywords:
cyclooxygenase 2; urothelial carcinoma; casein kinase 2α; Akt