- J Surg Res. 2009 May 3. [Epub ahead of print]
Inhibition of MIF Leads to Cell Cycle Arrest and Apoptosis in Pancreatic Cancer Cells.
Denz A, Pilarsky C, Muth D, Rückert F, Saeger HD, Grützmann R.
Department of Visceral-, Thoracic-, and Vascular Surgery, University Hospital Carl Gustav Carus, Dresden, Germany.
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.