1955-P: GLP-1R Activation Attenuates Prostate Cancer Growth via Inhibiting Cell Cycle Progression

Abstract

Incretin therapy is one of the most popular treatment for type 2 diabetes. We have previously reported anti-prostate cancer effect of GLP-1R agonist Exendin-4(Ex-4) (Diabetes 2014, PLOS ONE 2015), and LEADER trial suggested that GLP-1R agonist could reduce prostate cancer. In our previous report, the attenuation of prostate cancer cell proliferation was depending on GLP-1R expression, and Ex-4 did not attenuate cell proliferation in ALVA-41, a prostate cancer cell without intrinsic GLP-1R expression. Then, we next examined anti-prostate cancer effect in ALVA-41 forced expressed GLP-1R using lentivirus vector (ALVA-41-GLP-1R). We confirmed abundant GLP-1R expression in ALVA-41-GLP-1R using RT-PCR and immunohistochemistry, and intracellular cAMP level was increased by Ex-4 in ALVA-41-GLP-1R. Ex-4 significantly decreased the proliferation of ALVA-41-GLP-1R in a dose dependent manner, but not in ALVA-41-control. BrdU assay revealed that DNA synthesis was attenuated in ALVA-41-GLP-1R, and G1 to S phase entry was inhibited in cell cycle distribution in flow cytometry analysis. Further, p27kip protein was increased and Skp2, ubiquitin ligase for p27kip, expression was decreased in ALVA-41-GLP-1R treated by Ex-4. In vivo experiments using xenograft model mice transplanting ALVA-41-GLP-1R revealed that Ex-4 decreased prostate cancer growth via activation of GLP-1R forced expressed in ALVA41. Further, GLP-1R expression level in human prostate cancer tissues was inversely associated with Gleason grading system of human prostate cancer. These data suggested that forced expressed GLP-1R attenuated prostate cancer cell proliferation via inhibiting cell cycle progression in vivo and in vitro, and GLP-1R activation could be one of optional therapy for prostate cancer. Disclosure T. Shigeoka: None. T. Nomiyama: None. T. Kawanami: None. Y. Hamaguchi: None. T. Tanaka: None. S. Irie: None. K. Nabeshima: None. M. Tanaka: None. T. Yanase: None. Funding Japan Society for the Promotion of Science