title: Activation of glucagon-like peptide-1 receptor inhibits growth and promotes apoptosis of human pancreatic cancer cells in a cAMP-dependent manner.
abstract: Glucagon-like peptide-1 (GLP-1) promotes pancreatic β-cell regeneration through GLP-1 receptor (GLP-1R) activation. However, whether it promotes exocrine pancreas growth and thereby increases the risk of pancreatic cancer has been a topic of debate in recent years. Clinical data and animal studies published so far have been controversial. In the present study, we report that GLP-1R activation with liraglutide inhibited growth and promoted apoptosis in human pancreatic cancer cell lines in vitro and attenuated pancreatic tumor growth in a mouse xenograft model in vivo. These effects of liraglutide were mediated through activation of cAMP production and consequent inhibition of Akt and ERK1/2 signaling pathways in a GLP-1R-dependent manner. Moreover, we examined GLP-1R expression in human pancreatic cancer tissues and found that 43.3% of tumor tissues were GLP-1R-null. In the GLP-1R-positive tumor tissues (56.7%), the level of GLP-1R was lower compared with that in tumor-adjacent normal pancreatic tissues. Furthermore, the GLP-1R-positive tumors were significantly smaller than the GLP-1R-null tumors. Our study shows for the first time that GLP-1R activation has a cytoreductive effect on human pancreatic cancer cells in vitro and in vivo, which may help address safety concerns of GLP-1-based therapies in the context of human pancreatic cancer.
authors.affiliation: Department of Endocrinology and Metabolism and.
authors.forename: Hejun
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Endocrinology and Metabolism and.
authors.forename: Rui
authors.initials: R
authors.lastname: Wei
authors.affiliation: Department of Endocrinology and Metabolism and.
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Endocrinology and Metabolism and.
authors.forename: Qing
authors.initials: Q
authors.lastname: Tian
authors.affiliation: Department of General Surgery, Peking University Third Hospital, Beijing, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Tao
authors.affiliation: Department of Endocrinology and Metabolism and.
authors.forename: Jing
authors.initials: J
authors.lastname: Ke
authors.affiliation: Department of Endocrinology and Metabolism and.
authors.forename: Ye
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Endocrinology and Metabolism and.
authors.forename: Wenfang
authors.initials: W
authors.lastname: Hou
authors.affiliation: Department of Endocrinology and Metabolism and.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology and Metabolism and.
authors.forename: Jin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Endocrinology and Metabolism and tpho66@bjmu.edu.cn.
authors.forename: Tianpei
authors.initials: T
authors.lastname: Hong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D052216:Glucagon-Like Peptide 1 / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000069450:Liraglutide; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000819:agonists* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism; D046509:Tissue Culture Techniques; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D009363:Neoplasm Proteins; D018027:Receptors, Glucagon; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP
keywords: apoptosis; diabetes mellitus; glucagon-like peptide-1; pancreatic cancer; proliferation