The involvement of nuclear factor-kappa B in cyclooxygenase-2 overexpression in murine colon cancer cells transduced with herpes simplex virus thymidine kinase gene

A Konson, J A Mahajna, A Danon, G Rimon, R Agbaria
Cancer Gene Therapy 2006, 13 (12): 1093-104
We have previously reported that transduction of murine colon cancer cells (MC38) with herpes simplex virus thymidine kinase (HSV-tk) gene results in a significant enhancement of tumor growth rate in vivo and overexpression of cyclooxygenase-2 (COX-2). Our current study aimed to investigate the involvement of nuclear factor-kappa B (NF-kappaB), a pivotal transcriptional regulator of COX-2, in the upregulation of COX-2 expression by HSV-tk. It was found that HSV-tk gene transduction of MC38 cells results in significantly enhanced NF-kappaB activity, increased phosphorylation and degradation of inhibitor-kappa Balpha (IkappaBalpha) and enhanced translocation of NF-kappaB to the nucleus. Treatment of HSV-tk-transduced MC38 cells with sulfasalazine, a potent NF-kappaB inhibitor, led to dose-dependent inhibition of NF-kappaB activity, IkappaB phosphorylation and nuclear translocation of NF-kappaB, accompanied by significantly decreased COX-2 expression and reduced release of prostaglandin E2. Transient transfection experiments with COX-2 promoter constructs fused to luciferase reporter gene revealed that mutation in NF-kappaB-responsive element of COX-2 promoter significantly reduced promoter activity in HSV-tk-transduced MC38 and COS-7 cells, whereas it had no effect on promoter activity in the respective wild-type cells. At last, it was found that HSV-tk gene transduction causes significant enhancement of NF-kappaB activity and COX-2 expression in two additional tumor cell lines, 9L and T24. These findings suggest that HSV-tk gene transduction results in NF-kappaB pathway activation, which is essential for COX-2 overexpression by HSV-tk.

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