Pleiotropic benefits of incretin therapy beyond glycemic control have been reported and receiving much attention. Cancer is one of major causes of death in patients with type 2 diabetes. We have previously reported Exendin-4(Ex-4), a glucagon-like peptide-1 receptor agonist, attenuates prostate cancer growth by the inhibition of ERK-MAPK phosphorylation (Diabetes 2014). On the other hand, it is well known that MAPK is inactivated and tightly regulated by MAPK phosphatase (MKP) family. Then, we next examined whether MKP could be involved in the anti-proliferative effect of Ex-4 in the prostate cancer cell. In a human prostate cancer cell line, LNCaP cell, MKP-1 was abundantly expressed. Knocking down of MKP-1 using siRNA abolished Ex-4 induced-reduction of LNCaP cell number in growth curve. In addition, Ex-4 treatment significantly increased MKP-1 mRNA expression. To activate its phosphatase activity, Ser359 in the C terminus of MKP-1 is specifically phosphorylated. Ex-4 significantly phosphorylated Ser359 of MKP-1along with time course of dephosphorylating ERK-MAPK. Using Immunoprecipitation assay, we further confirmed that Ex-4 exactly phosphorylated Ser359 of MKP-1. In addition, if we transiently transfected GFP conjugated MKP-1 into LNCaP cells, nuclear translocation of MKP-1 induced by Ex-4 treatment was observed in early phase stimulation. These data suggest that Ex-4 attenuates prostate cancer cell proliferation via phosphorylation of MKP-1 followed by inhibition of ERK-MAPK activation.
T. Kawanami: None. T. Nomiyama: Research Support; Self; MSD K.K., Sanofi-Aventis, Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceuticals, Japan. Y. Hamaguchi: None. T. Tanaka: None. T. Yanase: Research Support; Self; MSD K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Pharmaceuticals, Japan.