Activation of glucagon-like peptide-1 receptor inhibits growth and promotes apoptosis of human pancreatic cancer cells in a cAMP-dependent manner

May 8, 2014American journal of physiology. Endocrinology and metabolism

Activating a hormone receptor slows growth and causes death of human pancreatic cancer cells through a cAMP-related process

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Abstract

GLP-1 receptor activation with liraglutide inhibited growth and promoted apoptosis in human pancreatic cancer cell lines.

Liraglutide attenuated pancreatic tumor growth in a mouse model.
The effects were mediated through GLP-1 receptor activation, leading to increased cAMP production.
Inhibition of the Akt and ERK1/2 signaling pathways was observed with GLP-1 receptor activation.
43.3% of human pancreatic cancer tissues were found to lack GLP-1 receptors.
GLP-1 receptor-positive tumors were significantly smaller than those lacking the receptor.

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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.

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Activation of glucagon-like peptide-1 receptor inhibits growth and promotes apoptosis of human pancreatic cancer cells in a cAMP-dependent manner

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