Abstract
Background: Prostate cancer progression is navigated by the androgen receptor (AR) and transforming-growth factor-β (TGF-β) signaling. We previously demonstrated that aberrant TGF-β signaling accelerates prostate tumor progression in a transgenic mouse model of prostate cancer via effects on epithelial-mesenchymal transition (EMT), driving castration-resistant prostate cancer (CRPC). Methods: This study examined the antitumor effect of the combination of TGF-β receptor I (TβRI) inhibitor, galunisertib, and FDA-approved antiandrogen enzalutamide, in our pre-clinical model. Age-matched genotypically characterized DNTGFβRII male mice were treated with either galunisertib and enzalutamide, in combination or as single agents in three “mini”-trials and the effects on tumor growth, phenotypic EMT, and actin cytoskeleton were evaluated. Results: Galunisertib in combination with enzalutamide significantly suppressed prostate tumor growth, by increasing apoptosis and decreasing cell proliferation of tumor cell populations compared to the inhibitor as a monotherapy (P < 0.05). The combination treatment dramatically reduced cofilin levels, actin cytoskeleton regulator, compared to single agents. Treatment with galunisertib targeted nuclear Smad4 protein (intracellular TGF-β effector), but had no effect on nuclear AR. Consequential to TGF-β inhibition there was an EMT reversion to mesenchymal-epithelial transition (MET) and re-differentiation of prostate tumors. Elevated intratumoral TGF-β1 ligand, in response to galunisertib, was blocked by enzalutamide. Conclusion: Our results provide novel insights into the therapeutic value of targeting TGF-β signaling to overcome resistance to enzalutamide in prostate cancer by phenotypic reprogramming of EMT towards tumor re-differentiation and cytoskeleton remodeling. This translational work is significant in sequencing TGF-β blockade and antiandrogens to optimize therapeutic response in CRPC.
| Original language | English |
|---|---|
| Pages (from-to) | 31-43 |
| Number of pages | 13 |
| Journal | Prostate |
| Volume | 79 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2019 |
Bibliographical note
Publisher Copyright:© 2018 Wiley Periodicals, Inc.
Funding
We acknowledge support of this work through funding from a Schwab Foundation Grant (NK, CP), National Institutes of Health grant K23CA197526 (CP), the James F. Hardymon Endowment in Urologic Research at the University of Kentucky (NK), and the National Center for Advancing Translational Sciences, UL1TR000117 (CAW). The authors thank Lorie Howard for assisting in the manuscript submission.
| Funders | Funder number |
|---|---|
| James F. Hardymon Endowment | |
| Schwab Foundation | |
| National Institutes of Health (NIH) | |
| National Childhood Cancer Registry – National Cancer Institute | K23CA197526 |
| National Center for Advancing Translational Sciences (NCATS) | UL1TR000117 |
| University of Kentucky |
Keywords
- EMT
- TGF-β inhibition strong
- enzalutamide
- therapeutic response
ASJC Scopus subject areas
- Oncology
- Urology
