Activation of overexpressed glucagon‐like peptide‐1 receptor attenuates prostate cancer growth by inhibiting cell cycle progression

Abstract

Aims/Introduction Incretin therapy is a common treatment for type 2 diabetes mellitus. We have previously reported an anti‐prostate cancer effect of glucagon‐like peptide‐1 receptor (GLP‐1R) agonist exendin‐4. The attenuation of cell proliferation in the prostate cancer cell line was dependent on GLP‐1R expression. Here, we examined the relationship between human prostate cancer severity and GLP‐1R expression, as well as the effect of forced expression of GLP‐1R using a lentiviral vector. Materials and Methods Prostate cancer tissues were extracted by prostatectomy and biopsy. GLP‐1R was overexpressed in ALVA‐41 cells using a lentiviral vector (ALVA‐41‐GLP‐1R cells). GLP‐1R expression was detected by immunohistochemistry and quantitative polymerase chain reaction. Cell proliferation was examined by growth curves and bromodeoxyuridine incorporation assays. Cell cycle distribution and regulators were examined by flow cytometry and western blotting. In vivo experiments were carried out using a xenografted model. Results GLP‐1R expression levels were significantly inversely associated with the Gleason score of human prostate cancer tissues. Abundant GLP‐1R expression and functions were confirmed in ALVA‐41‐GLP‐1R cells. Exendin‐4 significantly decreased ALVA‐41‐GLP‐1R cell proliferation in a dose‐dependent manner. DNA synthesis and G1‐to‐S phase transition were inhibited in ALVA‐41‐GLP‐1R cells. SKP2 expression was decreased and p27Kip1 protein was subsequently increased in ALVA‐41‐GLP‐1R cells treated with exendin‐4. In vivo experiments carried out by implanting ALVA‐41‐GLP‐1R cells showed that exendin‐4 decreased prostate cancer growth by activation of GLP‐1R overexpressed in ALVA41‐GLP‐1R cells. Conclusions Forced expression of GLP‐1R attenuates prostate cancer cell proliferation by inhibiting cell cycle progression in vitro and in vivo. Therefore, GLP‐1R activation might be a potential therapy for prostate cancer.

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“…Western blotting was performed as described previously [ 13 ]. The following primary antibodies were used: Cyclin D1 (#2978; Cell Signaling Technology, Danvers, MA, USA) and β-actin (sc-47778; Santa Cruz Biotechnology, Santa Cruz, CA, USA).…”

“…RT and quantitative real-time PCR were performed as described previously [ 13 ]. Each sample was analyzed in triplicate and normalized against hypoxanthine phosphoribosyltransferase ( HPRT ) mRNA expression.…”

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The Influence of Anti-Diabetic Drugs on Prostate Cancer

“…In the 30 human samples of PC GLP-1 receptor expression was inversely associated with cancer progression (Gleason score). Additionally in vitro and in vivo antiproliferative effects of GLP-1 receptors in ALVA-41 cells were evaluated and revealed that the presence of GLP-1 receptors inhibits PC cell proliferation by suppressing cell cycle progression [ 109 ]. Furthermore, the study of He and Li reveals that Exendin-4 sensitizes prostate cancer cells to radiation.…”