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Updated: Dec 30, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Exendin-4 enhances the sensitivity of prostate cancer to enzalutamide by targeting Akt activation
He Wenjing1, Yuanyuan Shao2, Yi Yu2
1Institute of Urology, the First Affiliated Hospital of Nanchang University, Nanchang, China.
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.
Insights
Glucagon-like peptide 1 (GLP-1) analog exendin-4 enhances prostate cancer sensitivity to enzalutamide. This combination therapy reduces tumor growth and overcomes resistance by inhibiting the Akt pathway.
Area of Science:
- Oncology
- Endocrinology
- Molecular Biology
Background:
- Glucagon-like peptide 1 (GLP-1) analogs are used for type 2 diabetes and show antitumor potential.
- Exendin-4 (Ex-4), a GLP-1 analog, previously inhibited prostate cancer cell growth by suppressing the PI3K/Akt/mTOR pathway.
- This pathway is activated by enzalutamide and linked to treatment resistance.
Purpose of the Study:
- To investigate if exendin-4 can enhance prostate cancer sensitivity to enzalutamide.
- To determine if exendin-4 can overcome enzalutamide resistance by inhibiting Akt activation.
Main Methods:
- Utilized LNCap and CWR22RV1 prostate cancer cell lines.
- Employed mice bearing xenografts derived from these cell lines.
- Administered exendin-4 and enzalutamide alone and in combination.
Main Results:
- Combination therapy dramatically suppressed tumor growth compared to enzalutamide alone.
- Exendin-4 antagonized enzalutamide-induced invasion and migration (P < .05).
- Combined treatment reduced Akt and mTOR levels and decreased nuclear AR localization more than monotherapy (P < .5).
Conclusions:
- Exendin-4 alleviates enzalutamide resistance in prostate cancer.
- Exendin-4 combined with enzalutamide may offer a more effective treatment for advanced prostate cancer.
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