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Activation of Glucagon-Like Peptide-1 Receptor Signaling Does Not Modify the Growth or Apoptosis of Human Pancreatic Cancer Cells

Department of Medicine, The Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada

Address correspondence and reprint requests to Dr. Daniel J. Drucker, Toronto General Hospital, Banting and Best Diabetes Centre, 200 Elizabeth St. MBRW4R-402, Toronto, Ontario, Canada M5G 2C4. E-mail: d.drucker{at}utoronto.ca

Abbreviations: BrdU, 5-bromo-2'-deoxyuridine; CREB, cAMP-responsive element–binding protein; DMEM, Dulbecco’s modified Eagle’s medium; EGF, epidermal growth factor; EGFR, EGF receptor; ERK, extracellular regulated kinase; Ex-4, exendin-4; FBS, fetal bovine serum; GLP, glucagon-like peptide; GLP-1R, GLP-1 receptor; Hsp90, heat shock protein 90; IBMX, 3-isobutyl-1-methylxanthine; PARP, poly(ADP-ribose) polymerase; PI 3-kinase, phosphatidylinositol 3-kinase; PMA, phorbol 12-myristate 13-acetate

Glucagon-like peptide (GLP)-1 promotes ß-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 Gs) 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.

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