Exendin‐4 enhances the sensitivity of prostate cancer to enzalutamide by targeting Akt activation

AbstractBackgroundGlucagon‐like peptide 1 (GLP‐1) and its analogs are first‐line choices for the treatment of type 2 diabetes mellitus. Recent studies have shown that they exhibit antitumor properties in some tumors. We previously found that a GLP‐1 analog, exendin‐4 (Ex‐4), inhibited the growth of prostate cancer cells through suppressing the PI3K/Akt/mTOR pathway, which is activated in response to enzalutamide treatment and reported to be closely related to resistance to enzalutamide. So we speculated that exendin‐4 may enhance the sensitivity of prostate cancer to enzalutamide through inhibiting Akt activation.MethodsLNCap and CWR22RV1 cell lines, as well as mice bearing xenografts formed from the two cells, were used.ResultsExendin‐4 in combination with enzalutamide dramatically suppressed tumor growth of prostate cancer cells compared to enzalutamide alone; exendin‐4 is capable of antagonizing enzalutamide‐induced invasion and migration of both prostate cancer cells (P < .05). Furthermore, the combination treatment significantly reduced Akt and mTOR levels that were triggered by enzalutamide administration, caused a further decrease in nuclear AR localization compared with the enzalutamide as a monotherapy (P < .5), though exendin‐4 treatment alone showed no effect on nuclear AR.ConclusionOur study demonstrated that exendin‐4 alleviated resistance to enzalutamide, and suggested that exendin‐4 combined with enzalutamide may be a more efficacious treatment for patients with advanced prostate cancer.