Activation of GLP-1 receptor enhances the chemosensitivity of pancreatic cancer cells

Abstract

This study aimed to determine whether and how the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide affects the chemoresistance and chemosensitivity of pancreatic cancer cells to gemcitabine in vitro and in vivo. The GLP-1R and protein kinase A (PKA) levels were compared between the human pancreatic cancer cell line PANC-1 and the gemcitabine-resistant cell line PANC-GR. The in vitro effects of liraglutide on the cell proliferation and apoptosis as well as the nuclear factor-kappa B NF-κB expression levels of PANC-GR cells were evaluated. In addition, a mouse xenograft model of human pancreatic cancer was established by s.c. injection of PANC-1 cells, and the effects of liraglutide on the chemosensitivity were evaluated in vitro and in vivo. In contrast to PANC-1 cells, PANC-GR cells exhibited lower expression levels of GLP-1R and PKA. Incubation with liraglutide dose dependently inhibited the growth, promoted the apoptosis, and increased the expression of GLP-1R and PKA of PANC-GR cells. Similar effects of liraglutide were observed in another human pancreatic cancer cell line MiaPaCa-2/MiaPaCa-2-GR. Either the GLP-1R antagonist Ex-9, the PKA inhibitor H89, or the NF-κB activator lipopolysaccharide (LPS) could abolish the antiproliferative and proapoptotic activities of liraglutide. Additionally, each of these agents could reverse the expression of NF-κB and ABCG2, which was decreased by liraglutide treatment. Furthermore, liraglutide treatment increased the chemosensitivity of pancreatic cancer cells to gemcitabine, as evidenced by in vitro and in vivo experiments. Thus, GLP-1R agonists are safe and beneficial for patients complicated with pancreatic cancer and diabetes, especially for gemcitabine-resistant pancreatic cancer.

Analysis of the Prognosis Related Genes in HER2+ Breast Cancer Based on Weighted Gene Co-expression Network Analysis

“…GLP1R (Glucagon Like Peptide 1 Receptor) is a Protein Coding gene which is a member of G protein coupled receptor family. GLP-1R is an important target when treating of type 2 diabetes and obesity [32][33][34]. Recent studies have shown that GLP-1R activation has a cytoreductive effect on human pancreatic cancer cells [35].…”

GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects

“…Zhang et al. reported for the first time that liraglutide exhibited significant anti-proliferation and pro-apoptotic effects on gemcitabine-resistant human pancreatic cancer cells resistant to a variety of drugs, by regulating the NF-κB signaling pathway and downstream ATP-binding cassette subfamily G member 2 (ABCG2) ( 213 , 214 ).…”

“…Similarly, GLP-1RAs were also demonstrated to exert an inhibitory effect on the growth of breast and cervical cancer, implying the potential application of GLP-1RAs for the treatment of these cancer (10). Zhang et al reported for the first time that liraglutide exhibited significant anti-proliferation and pro-apoptotic effects on gemcitabine-resistant human pancreatic cancer cells resistant to a variety of drugs, by regulating the NF-kB signaling pathway and downstream ATP-binding cassette subfamily G member 2 (ABCG2) (213,214).…”

Exendin-4 — A potential therapeutic for type 2 diabetes-linked cervical cancer?

“…For instance, a meta-analysis of randomized, controlled trials involving 63 594 patients with T2D indicated that treatment with albiglutide (a GLP-1 agonist) was associated with a 24% reduction of all sites of cancer when compared to the placebo group [6]. Moreover, in prostate cancer patients, Exendin-4 has been shown to enhance the responsiveness to chemotherapy and reduce cancer growth [7]. In addition to its blood glucoselowering effect, the GLP-1 mimetic exerts an anti-inflammatory effect on a variety of tissues and organs in the body [8].…”

“…As inflammation plays a key role in the development of many cancer types, it is possible that this understated anti-cancer effect of the GLP-1 mimetic is linked to its anti-inflammatory effect. Of note, the GLP-1 mimetic is reported to inhibit pancreatic and breast cancer cell proliferation through the inhibition of the NF-kB pathway in experimental studies [7,9].…”