Exendin-4, a GLP-1 Receptor Agonist, Attenuates Prostate Cancer Growth

Abstract

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 anticancer effects of incretin. Here, we examined the effect of the incretin drug exendin (Ex)-4, a GLP-1 receptor (GLP-1R) agonist, on prostate cancer. In human prostate cancer tissue obtained from patients after they had undergone radical prostatectomy, GLP-1R expression colocalized with P504S, a marker of prostate cancer. In in vitro experiments, Ex-4 significantly decreased the proliferation of the prostate cancer cell lines LNCap, PC3, and DU145, but not that of ALVA-41. This antiproliferative 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 small interfering RNA abolished the inhibitory effect of Ex-4 on cell proliferation. Although Ex-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, Ex-4 attenuated in vivo prostate cancer growth induced by transplantation of LNCap cells into athymic mice and significantly reduced the tumor expression of P504S, Ki67, and phosphorylated ERK-MAPK. These data suggest that Ex-4 attenuates prostate cancer growth through the inhibition of ERK-MAPK activation.

Dipeptidyl peptidase-4 inhibitor linagliptin attenuates neointima formation after vascular injury

“…On the other hand, we have previously reported the vascular-protective effects of exendin-4, a GLP-1R agonist, including attenuation of atheroma formation in apoE-deficient mice via inhibition of NFκB activation in macrophages [17], and reduction of neointima formation after vascular injury via 5′ AMP-activated protein kinase activation in VSMCs [18]. Furthermore, we have recently demonstrated the anti-cancer effect of exendin-4 using a prostate cancer model [19]. However, recent clinical studies have unfortunately failed to prove cardiovascular benefits of DPP-4 inhibitors in patients with prior cardiovascular events using saxagliptin [20] or alogliptin [21].…”

Sitagliptin may reduce prostate cancer risk in male patients with type 2 diabetes

“…The Japanese investigators showed that GLP-1R is expressed in human prostate cancer tissue and exendin-4 (a GLP-1R agonist) significantly decreased the proliferation of prostate cancer cells that expressed GLP-1R [26, 27]. Such antiproliferative effect of exendin-4 on prostate cancer was not via androgen receptor, but through the inhibition of extracellular signal–regulated kinase-mitogen-activated protein kinase (ERK-MAPK) phosphorylation via GLP-1R [26]. This inhibitory effect on ERK-MAPK was mediated by the cyclic adenosine 3′,5′-monophosphate-protein kinase A pathway and was not dependent on adenosine monophosphate activated protein kinase activation or Akt phosphorylation [26].…”

“…Such antiproliferative effect of exendin-4 on prostate cancer was not via androgen receptor, but through the inhibition of extracellular signal–regulated kinase-mitogen-activated protein kinase (ERK-MAPK) phosphorylation via GLP-1R [26]. This inhibitory effect on ERK-MAPK was mediated by the cyclic adenosine 3′,5′-monophosphate-protein kinase A pathway and was not dependent on adenosine monophosphate activated protein kinase activation or Akt phosphorylation [26]. In an in vivo study, exendin-4 also attenuated the growth of prostate cancer cells transplanted to athymic mice via the inhibition of ERK-MAPK activation [26].…”

“…This inhibitory effect on ERK-MAPK was mediated by the cyclic adenosine 3′,5′-monophosphate-protein kinase A pathway and was not dependent on adenosine monophosphate activated protein kinase activation or Akt phosphorylation [26]. In an in vivo study, exendin-4 also attenuated the growth of prostate cancer cells transplanted to athymic mice via the inhibition of ERK-MAPK activation [26]. In humans, administration of sitagliptin 50 mg per day for 3 days significantly increased active GLP-1 level by 2.5–fold [28].…”

Exendin-4 Exhibits Enhanced Anti-tumor Effects in Diabetic Mice

“…T2D is associated with reduced incretin effects, although the secretion of GLP-1 is not always decreased 7, 8 . Pharmacoepidemiological studies have shown that exendin-4 exerts anti-tumor effects in human pancreatic cancer cells and prostate cancer cells 9, 10 . Furthermore, GLP-1 receptor expression is widely detected in various cells and organs including kidney, lung, heart, hypothalamus, endothelial cells, neurons, astrocytes, microglia and pancreatic beta-cells as well as immune cells 11–14 .…”