Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Calcium-Calmodulin-Dependent Protein Kinases / physiology
-
Carcinoma / enzymology
-
Carcinoma / pathology*
-
Cell Cycle / drug effects
-
Cell Cycle Proteins*
-
Culture Media, Serum-Free / pharmacology
-
Cyclin D1 / biosynthesis*
-
Cyclin D1 / genetics
-
Cyclin E / metabolism
-
Cyclin-Dependent Kinase Inhibitor p27
-
Humans
-
Microtubule-Associated Proteins / metabolism
-
Mitogen-Activated Protein Kinase 1
-
Neoplasm Proteins / antagonists & inhibitors
-
Neoplasm Proteins / physiology*
-
Pancreatic Neoplasms / enzymology
-
Pancreatic Neoplasms / pathology*
-
Phosphorylation / drug effects
-
Phosphotransferases (Alcohol Group Acceptor) / physiology*
-
Protein Kinases*
-
Protein Processing, Post-Translational / drug effects
-
Ribosomal Protein S6 Kinases / physiology*
-
Signal Transduction / physiology*
-
Sirolimus / pharmacology*
-
TOR Serine-Threonine Kinases
-
Tumor Cells, Cultured / drug effects
-
Tumor Cells, Cultured / metabolism
-
Tumor Suppressor Proteins*
Substances
-
Cell Cycle Proteins
-
Culture Media, Serum-Free
-
Cyclin E
-
Microtubule-Associated Proteins
-
Neoplasm Proteins
-
Tumor Suppressor Proteins
-
Cyclin D1
-
Cyclin-Dependent Kinase Inhibitor p27
-
Protein Kinases
-
Phosphotransferases (Alcohol Group Acceptor)
-
MTOR protein, human
-
Ribosomal Protein S6 Kinases
-
TOR Serine-Threonine Kinases
-
Calcium-Calmodulin-Dependent Protein Kinases
-
Mitogen-Activated Protein Kinase 1
-
Sirolimus