Glucagon-like peptide-2 does not modify the growth or survival of murine or human intestinal tumor cells.
Glucagon-like peptide-2 (GLP-2) secreted from enteroendocrine cells exerts proabsorptive, regenerative, and cytoprotective actions in the normal and injured gut epithelium. Hence, sustained GLP-2 receptor (GLP-2R) activation represents a strategy under investigation for the prevention and treatment of chemotherapy-induced mucositis. Nevertheless, the consequences of increased GLP-2R signaling for the growth and survival of intestinal tumor cells remain poorly understood. We studied the proliferative and cytoprotective actions of GLP-2 in human colon cancer cells stably transfected with the GLP-2R and in nude mice harboring GLP-2R(+) human colon cancer cells. The importance of the GLP-2R for tumor growth was also examined in Apc(Min/+) mice chronically treated with exogenous GLP-2 and in Apc(Min/+):Glp2r(-/-) mice. GLP-2 increased cyclic AMP accumulation and produced cell-specific activation of growth and survival pathways in DLD-1, SW480, and HT29 cells. However, GLP-2 did not stimulate cell growth or attenuate cycloheximide-, LY294002-, indomethacin-, or chemotherapy-induced cytotoxicity in vitro. Moreover, chronic GLP-2 administration had no effect on the growth of human colon cancer cell xenografts in nude mice in vivo. Daily GLP-2 treatment for 7 weeks increased growth of normal gut mucosa but did not increase the number or size of polyps in Apc(Min/+) mice, and genetic disruption of the Glp2r gene in Apc(Min/+) mice did not modify polyp size or number. Taken together, although GLP-2R activation engages signaling pathways promoting cell proliferation and cytoprotection in the normal gut epithelium, sustained direct or indirect modulation of GLP-2R signaling does not modify intestinal tumor cell growth or survival.
Koehler
Jacqueline A
JA
Department of Medicine, Samuel Lunenfeld Research Institute, Mt Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
Harper
Will
W
Barnard
Maja
M
Yusta
Bernardo
B
Drucker
Daniel J
DJ
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D017491:Genes, APC; D053767:Glucagon-Like Peptide 2 / Q000494:pharmacology*; D000067758:Glucagon-Like Peptide-2 Receptor; D019073:HT29 Cells; D006801:Humans; D007414:Intestinal Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D053767:Glucagon-Like Peptide 2; D000067758:Glucagon-Like Peptide-2 Receptor; D018027:Receptors, Glucagon