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

BACKGROUND: Glucagon-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. METHODS: LNCap and CWR22RV1 cell lines, as well as mice bearing xenografts formed from the two cells, were used. RESULTS: Exendin-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. CONCLUSION: Our 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.