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.
II. Medizinische Klinik, Technische Universität München, Ismaninger Str. 22, D-81675 München, Germany.
Susanne
S
Schüler
Sandra
S
Diersch
Rainer
R
Hamacher
Roland M
RM
Schmid
Dieter
D
Saur
Günter
G
Schneider
D017209:Apoptosis / Q000187:drug effects*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D044786:S-Phase Kinase-Associated Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand