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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.

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Steroidogenic factor 1 (SF-1)/adrenal 4 binding protein is an essential nuclear receptor for steroidogenesis, as well as for adrenal and gonadal gland development. We have previously clarified that adenovirus-mediated forced expression of SF-1 can transform long-term cultured mouse bone marrow mesenchymal cells (BMCs) into ACTH-responsive steroidogenic cells. In the present study, we extended this work to adipose tissue-derived mesenchymal cells (AMCs) and compared its steroidogenic capacity with those of BMCs prepared from the identical mouse. Several cell surface markers, including potential mesenchymal cell markers, were identical in both cell types, and, as expected, forced expression of SF-1 caused AMCs to be transformed into ACTH-responsive steroidogenic cells. However, more elaborate studies revealed that the steroidogenic property of AMCs was rather different from that of BMCs, especially in steroidogenic lineage. In response to increased SF-1 expression and/or treatment with retinoic acid, AMCs were much more prone to produce adrenal steroid, corticosterone rather than gonadal steroid, testosterone, whereas the contrary was evident in BMCs. Such marked differences in steroidogenic profiles between AMCs and BMCs were also evident by the changes of steroidogenic enzymes. These novel results suggest a promising utility of AMCs for autologous cell regeneration therapy for patients with steroid insufficiency and also a necessity for appropriate tissue selection in preparing mesenchymal stem cells according to the aim. The different steroidogenic potency of AMCs or BMCs might provide a good model for the clarification of the mechanism of tissue- or cell-specific adrenal and gonadal steroidogenic cell differentiation.