Glucagon-like peptide-2 does not modify the growth or survival of murine or human intestinal tumor cells.

Abstract

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.

• Authors: Jacqueline A Koehler, Will Harper, Maja Barnard, Bernardo Yusta, Daniel J Drucker
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 19 Pg. 7897-904 (Oct 01 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18829546 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glucagon-Like Peptide 2
• Glucagon-Like Peptide-2 Receptor
• Receptors, Glucagon

Topics

• Animals
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Female
• Genes, APC
• Glucagon-Like Peptide 2 (pharmacology)
• Glucagon-Like Peptide-2 Receptor
• HT29 Cells
• Humans
• Intestinal Neoplasms (metabolism, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Nude
• Receptors, Glucagon (genetics, metabolism)
• Tumor Cells, Cultured