Recently, pleiotropic benefits of incretin therapy beyond glycemic control have been reported. Although cancer is one of the main causes of death in diabetic patients, few reports describe the anti-cancer effects of incretin. Here, we examined the effect of the incretin drug Exendin-4, a glucagon-like peptide-1 receptor (GLP-1R) agonist, on prostate cancer. In human prostate cancer tissue obtained from patients after radical prostatectomy, GLP-1R expression co-localized with P504S, a marker of prostate cancer. In in vitro experiments, Exendin-4 significantly decreased proliferation of the prostate cancer cell lines, LNCaP, PC3 and DU145, but not that of ALVA-41. This anti-proliferative effect depended on GLP-1R expression. In accordance with the abundant expression of GLP-1R in LNCaP cells, a GLP-1R antagonist or GLP-1R knockdown with siRNA abolished the inhibitory effect of Exendin-4 on cell proliferation. Although Exendin-4 had no effect on either androgen receptor activation or apoptosis, it decreased extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) phosphorylation in LNCaP cells. Importantly, Exendin-4 attenuated in vivo prostate cancer growth induced by transplantation of LNCaP cells into athymic mice and significantly reduced tumor expression of P504S, Ki67 and phosphorylated ERK-MAPK. These data suggest that Exendin-4 attenuates prostate cancer growth through inhibition of ERK-MAPK activation.
# These authors contributed equally to this work.
- Received July 29, 2013.
- Accepted May 27, 2014.
- © 2014 by the American Diabetes Association.
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