TRANSCRIPT PROFILING IDENTIFIES NOVEL KEY PLAYERS MEDIATING THE GROWTH INHIBITORY EFFECT OF NS-398 ON HUMAN PANCREATIC CANCER CELLS Research Title

Pancreatic cancer is one of the most aggressive human malignancies with an increasing incidence worldwide. Despite an increase in the number of systemic treatments available for pancreatic cancer. the impact of therapy on the clinical course of the disease has been modest. underscoring an urgent need for new therapeutic options. Although selective cyclooxygenase-2 inhibitors have been demonstrated to have cancerpreventive effects. the mechanism of their effects is not clearly known. Moreover, there have been no unbiased studies to identify novel molecular targets of NS-398 regarding pancreatic cancer. Here we undertook a gene expression profiling study to identify novel molecular targets modulating the growth inhibitory effects ofNS-398 on pancreatic cancer cell lines. Our mRNA-based gene expression results showed that the growth inhibitory effect of NS-398 was accompanied with an activation of Gl/S and G2/M cell cycle regulation. PS3 signalling. apoptotic, aryl hydrocarbon receptor and death receptor signalling pathways. Moreover. we reported. for the first time. that the growth inhibitory effect of NS-398 is mediated by down regulation of RRM2. CfGF. MCM2 and PCNA and up-regulation of NAG-l in all cell lines.