16 research outputs found
The disruption of protein-protein interactions as a therapeutic strategy for prostate cancer
This is an accepted manuscript of an article published by Elsevier in Pharmacological Research on 16/08/2020, available online: https://doi.org/10.1016/j.phrs.2020.105145
The accepted version of the publication may differ from the final published version.Prostate cancer (PCa) is one of the most common male-specific cancers worldwide, with high morbidity and mortality rates associated with advanced disease stages. The current treatment options of PCa are prostatectomy, hormonal therapy, chemotherapy or radiotherapy, the selection of which is usually dependent upon the stage of the disease. The development of PCa to a castration-resistant phenotype (CRPC) is associated with a more severe prognosis requiring the development of a new and effective therapy. Protein-protein interactions (PPIs) have been recognised as an emerging drug modality and targeting PPIs is a promising therapeutic approach for several diseases, including cancer. The efficacy of several compounds in which target PPIs and consequently impair disease progression were validated in phase I/II clinical trials for different types of cancer. In PCa, various small molecules and peptides proved successful in inhibiting important PPIs, mainly associated with the androgen receptor (AR), Bcl-2 family proteins, and kinases/phosphatases, thus impairing the growth of PCa cells in vitro. Moreover, a majority of these compounds require further validation in vivo and, preferably, in clinical trials. In addition, several other PPIs associated with PCa progression have been identified and now require experimental validation as potential therapeutic loci.
In conclusion, we consider the disruption of PPIs to be a promising though challenging therapeutic strategy for Pca. Agents which modulate PPIs might be employed as a monotherapy or as an adjunct to classical chemotherapeutics to overcome drug resistance and improve efficacy. The discovery of new PPIs with important roles in disease progression, and of novel optimized strategies to target them, are major challenges for the scientific and pharmacological communities.We thank the Portuguese Foundation for Science and Technology(FCT), European Union, QREN, FEDER and COMPETE for funding iBiMED (UIDB/04501/2020, POCI-01-0145-FEDER-23007628 and UID/BIM/04501/2019) and an individual scholarship from BM (SFRH/BD/146032/2019)
YAP1 and AR interactions contribute to the switch from androgen-dependent to castration-resistant growth in prostate cancer.
YAP1 and AR interactions contribute to the switch from androgen-dependent to castration-resistant growth in prostate cancer.
The transcriptional co-activator Yes-associated protein 1 (YAP1), a key nuclear effector of the Hippo pathway, is a potent oncogene, and yet, the interaction between YAP1 and androgen receptor (AR) remains unexplored. Here we identify YAP1 as a physiological binding partner and positive regulator of AR in prostate cancer. YAP1 and AR co-localize and interact with each other predominantly within cell nuclei by an androgen-dependent mechanism in a hormone naive and an androgen-independent mechanism in castration-resistant prostate cancer cells. The growth suppressor MST1 kinase modulates androgen-dependent and -independent nuclear YAP1-AR interactions through directly regulating YAP1 nuclear accumulation. Disruption of YAP1 signalling by genetic (RNAi) and pharmacological (Verteporfin) approaches suppresses AR-dependent gene expression and prostate cancer cell growth. These findings indicate that the YAP1-AR axis may have a critical role in prostate cancer progression and serves as a viable drug target