https://orcid.org/0000-0002-8864-1560
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ABSTRACT
Castrate-resistant prostate cancer (CRPC) is challenging to treat, despite improvements with next-generation anti-androgens such as enzalutamide, due to acquired resistance. One of the mechanisms of such resistance includes aberrant activation of co-factors of the androgen receptor (AR), such as the serum response factor (SRF), which was associated with prostate cancer progression and resistance to enzalutamide. Here, we show that inhibition of SRF with three small molecules (CCG-1423, CCG-257081 and lestaurtinib), singly and in combination with enzalutamide, reduces cell viability in an isogenic model of CRPC. The effects of these inhibitors on the cell cycle, singly and in combination with enzalutamide, were assessed with western blotting, flow cytometry and β-galactosidase staining. In the androgen deprivation-sensitive LNCaP parental cell line, a synergistic effect between enzalutamide and all three inhibitors was demonstrated, while the androgen deprivation-resistant LNCaP Abl cells showed synergy only with the lestaurtinib and enzalutamide combination, suggesting a different mechanism of action of the CCG series of compounds in the absence and presence of androgens. Through analysis of cell cycle checkpoint proteins, flow cytometry and β-galactosidase staining, we showed that all three SRF inhibitors, singly and in combination with enzalutamide, induced cell cycle arrest and decreased S phase. While CCG-1423 had a more pronounced effect on the expression of cell cycle checkpoint proteins, CCG-257081 and lestaurtinib decreased proliferation also through induction of cellular senescence. In conclusion, we show that inhibition of an AR co-factors, namely SRF, provides a promising approach to overcoming resistance to AR inhibitors currently used in the clinic.
Acknowledgements
We would like to thank Dr. Alfonso Blanco, Director of the Flow Cytometry Core Technology Unit at University College Dublin for his expert guidance and Dr Erika Lisabeth, Department of Pharmacology & Toxicology, Michigan State University for supplying the CCG257081 inhibitor.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Author contributions
HA: investigation, formal analysis, writing (original draft); SM: investigation, formal analysis, writing (review & editing), SC: investigation, formal analysis, writing (review & editing); WMG: validation, writing (review & editing); MP: conceptualization, data curation, validation, writing (review & editing), visualization, supervision, funding acquisition, project administration. All authors have read and agreed to the published version of the manuscript.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/15384101.2023.2229713