Activation of glucagon-like peptide-1 receptor signaling does not modify the growth or apoptosis of human pancreatic cancer cells.
Glucagon-like peptide (GLP)-1 promotes beta-cell proliferation and survival through stimulation of its specific G-protein-coupled receptor; however, the potential for GLP-1 receptor (GLP-1R) agonists to promote growth and proliferation of human pancreatic-derived cells remains poorly understood. We identified five human pancreatic cancer cell lines that express the GLP-1R and analyzed cell growth and survival in response to GLP-1R activation. Although cholera toxin (an activator of Galphas) and forskolin (an activator of adenylyl cyclase) increased levels of intracellular cAMP in all cell lines, the GLP-1R agonist exendin-4 (Ex-4) increased cAMP only in CFPAC-1 cells. Conversely, Ex-4 induced extracellular regulated kinase (ERK) 1/2 activation in PL 45 cells in a GLP-1R-and epidermal growth factor receptor-dependent manner, whereas Ex-4 inhibited ERK1/2 phosphorylation in Hs 766T and CAPAN-1 cells. Ex-4 did not modulate the proliferation of these cell lines in vitro and did not inhibit apoptosis after exposure of cells to cytotoxic agents such as cycloheximide, indomethacin, LY294002, or cyclopamine. Furthermore, daily Ex-4 treatment for 4 weeks had no effect on the propagation of CFPAC-1 or PL 45 tumor cells evaluated in nude mice in vivo. Thus, acute or chronic (4 weeks) GLP-1R stimulation does not modify the growth or survival of human pancreatic cancer cells.
Koehler
Jacqueline A
JA
Banting and Best Diabetes Centre, Toronto General Hospital, 200 Elizabeth St. MBRW4R-402, Toronto, Ontario, Canada M5G 2C4.
Drucker
Daniel J
DJ
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002772:Cholera Toxin / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D003516:Cycloparaffins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000503:physiopathology*; D018027:Receptors, Glucagon / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D002867:Chromones; D003516:Cycloparaffins; D004791:Enzyme Inhibitors; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D009025:Morpholines; D018027:Receptors, Glucagon; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D002772:Cholera Toxin; D003513:Cycloheximide; D048052:Mitogen-Activated Protein Kinase 3; D007213:Indomethacin