Downregulation of Dipeptidyl Peptidase 4 Accelerates Progression to Castration-Resistant Prostate Cancer
Abstract
The standard treatment for metastatic prostate cancer, androgen deprivation therapy (ADT), is designed to suppress androgen receptor (AR) activity. However, men invariably progress to castration-resistant prostate cancer (CRPC), and AR reactivation contributes to progression in most cases. To identify mechanisms that may drive CRPC, we examined a VCaP prostate cancer xenograft model as tumors progressed from initial androgen sensitivity prior to castration to castration resistance and then on to relapse after combined therapy with further AR-targeted drugs (abiraterone plus enzalutamide). AR activity persisted in castration-resistant and abiraterone/enzalutamide–resistant xenografts and was associated with increased expression of the AR gene and the AR-V7 splice variant. We then assessed expression of individual AR-regulated genes to identify those that persisted, thereby contributing to tumor growth, versus those that decreased and may therefore exhibit tumor suppressor activities. The most significantly decreased AR target gene was dipeptidyl peptidase 4 (DPP4), which encodes a membrane-anchored protein that cleaves dipeptides from multiple growth factors, resulting in their increased degradation. DPP4 mRNA and protein were also decreased in clinical CRPC cases, and inhibition of DPP4 with sitagliptin enhanced the growth of prostate cancer xenografts following castration. Significantly, DPP4 inhibitors are frequently used to treat type 2 diabetes as they increase insulin secretion. Together, these results implicate DPP4 as an AR-regulated tumor suppressor gene whose loss enhances growth factor activity and suggest that treatment with DPP4 inhibitors may accelerate emergence of resistance to ADT.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 15, 2018
- Source ID
- 10.1158/0008-5472.can-18-0687
Entities
People
- Bruce Montgomery
- Carla Calagua
- Ce Gao
- Elahe A. Mostaghel
- Eva Corey
- Huihui Ye
- Joshua W. Russo
- Manoj Bhasin
- Mary-ellen Taplin
- Olga S. Voznesensky
- Peter S Nelson
- Seiji Arai
- Steven P Balk
- Swati S. Bhasin
Organizations
- Congressionally Directed Medical Research Programs
- Gunma University Hospital
- Harvard Medical School
- National Cancer Institute
- Prostate Cancer Foundation