IKK1 promotes G1 phase progression of pancreatic cancer cells by the transcriptional regulation of the F-box protein skp2

Pancreatic cancer is one of the most lethal human cancers. Advances in cancer biology have improved the understanding of the pathogenesis of pancreatic cancer, but the diseases prognosis, with a five year overall survival below 5% is any longer extreme poor. The IKK consist of the catalytical subunits IKK1 and IKK2 and the structural subunit Nemo. This kinase is constitutive active in pancreatic cancer cells and regulates proliferative and anti-apoptotic programs. The functions of the individual catalytical subunits in pancreatic cancer cells are so far unknown. Functional genomics using RNA interference was used to study the contribution of the cytalytical IKK subunits IKK1 and IKK2 to proliferative and anti-apoptotic programs in pancreatic cancer cell lines. Neither the knockdown of the IKK1 nor the knockdown of the IKK2 catalytical IKK subunit induces overt apoptosis 48 hours after the transfection of the specific siRNAs. However a definite reduction of proliferation was observed after the transfection of the IKK1 specific siRNAs in pancreatic cancer cell lines. The IKK2 knockdown has no effect onto the BrdU incorporation. FACS analysis demonstrates an accumulation of cells in the G1 Phase of the cell cycle, without changes in cyclin D1 mRNA and protein abundances after the knockdown of the IKK1. Otherwise the protein abundance of the cyclin-dependent kinase inhibitor p27Kip1 is increased in IKK1 siRNA transfected pancreatic cancer cells. The elevated expression of p27Kip1 leads to the activation of the G1 checkpoint regulators Rb and Rb2, explaining the accumulation of cells in the G1 phase of the cell cycle. The cause of the increase of p27Kip1 is the transcriptional regulation of the F-box protein skp2 by IKK1. Together, this work defines a novel IKK1 regulated growth pathway involving the transcriptional regulation of the skp2 gene and destabilization of p27Kip1 in pancreatic cancer cells.

Keywords: IKK1 cell cycle pancreatic cancer skp2 p27Kip1