Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP-p70s6K pathway in human pancreatic cancer cells.
The FRAP-p70s6K signaling pathway was found to be constitutively phosphorylated/active in MiaPaCa-2 and Panc-1 human pancreatic cancer cells and a pancreatic cancer tissue sample as judged by the retarded electrophoretic mobility of the two major FRAP downstream targets, p70s6K and 4E-BP1. Treatment of cells with rapamycin, a selective FRAP Inhibitor, inhibited basal p70s6K kinase activity and induced dephosphorylation of p70s6K and 4E-BP1. Moreover, rapamycin inhibited DNA synthesis as well as anchorage-dependent and -independent proliferation in MiaPaCa-2 and Panc-1 cells. Finally, rapamycin strikingly inhibited cyclin D1 expression in pancreatic cancer cells. Thus, inhibitors of the constitutively active FRAP-p70s6K pathway may provide a novel therapeutic approach for pancreatic cancer.
Grewe
M
M
Department of Internal Medicine I, University of Ulm, Germany.
Gansauge
F
F
Schmid
R M
RM
Adler
G
G
Seufferlein
T
T
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D002277:Carcinoma / Q000201:enzymology / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics; D019927:Cyclin E / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D011494:Protein Kinases; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D019893:Ribosomal Protein S6 Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D016895:Culture Media, Serum-Free; D019927:Cyclin E; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011494:Protein Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); C546842:MTOR protein, human; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020123:Sirolimus