SKP2 confers resistance of pancreatic cancer cells towards TRAIL-induced apoptosis.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dismal prognosis and no effective conservative therapy exists. Although the F-box protein S-phase kinase associated protein 2 (SKP2) is highly expressed and regulates cell cycle progression in PDAC, alternative SKP2 functions in PDAC are unknown. Using RNA interference we now demonstrate that SKP2 confers resistance of a subset of PDAC cell lines towards the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), but not the topoisomerase II inhibitor etoposide. We observed accelerated cleavage of the BH3-only protein Bid and augmented downregulation of cFLIPL, XIAP and MCL1 upon treatment of SKP2-depleted MiaPaCa2 cells with TRAIL. Our data disclose a novel SKP2 function in PDAC cells and therefore define SKP2 as a molecular target.