Inhibition of MIF leads to cell cycle arrest and apoptosis in pancreatic cancer cells.

BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is the eighth most common cancer with the lowest overall 5-y relative survival rate. Gene expression profiling of PDAC revealed an overexpression of the macrophage migration inhibitory factor (MIF), a lymphokine involved in cell-mediated immunity and inflammation, as well as in the regulation of cellular signal transduction. MATERIALS AND METHODS Endogenous MIF expression was silenced by treatment of pancreatic cancer cell lines using two independent MIF siRNAs. The expression of MIF RNA and protein after siRNA treatment was investigated using quantitative RT-PCR and Western blot. Induction of apoptosis was analyzed using fluorescence activated cell sorting (FACS). RESULTS Transfection of MiaPaCa-2 cells with MIF siRNA resulted in a reduction of MIF RNA and protein levels by more than 85%. After treatment, we observed an inhibition of cellular proliferation accompanied by induction of apoptosis. Analysis of the phosphorylation state of Akt showed a markedly increase of the phosphorylation at the Thr308 residue. CONCLUSIONS Using post-transcriptional silencing with small interfering RNAs, we could show that MIF acts as an autocrine growth factor involved in cell cycle progression. Since MIF is a secreted protein, a therapy directed against MIF or its receptor might lead to a significant growth reduction of PDAC.