The disruption of protein-protein interactions as a therapeutic strategy for prostate cancer

Abstract

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.

TPX2 Enhanced the Activation of the HGF/ETS-1 Pathway and Increased the Invasion of Endocrine-Independent Prostate Carcinoma Cells

“…The prognosis for endocrine-independent prostate carcinoma (PC) is still poor due to its insensitivity to androgen deprivation therapy (ADT) or its highly metastatic feature (1). Therefore, it is valuable to explore the detailed mechanisms of resistance and progression in endocrine-independent PC cells, with specific focus on the molecular alterations that participate in the activation of androgen receptor (AR)-independent pathways (2,3).…”

The fork restart factor PHF6 interacts with RRM2 and binds to H3K56ac marked nascent DNA

“…Through NanoBRET ™ -based deletion mapping, we could pinpoint the first PHD domain of PHF6 as critical interface for the physical interaction with RRM2. Protein-protein interactions are increasingly recognized as an emerging drug modality and therefore we propose that pharmacological targeting PHF6-RRM2 is a promising therapeutic approach in cancer 62 . Given that we previously identified RRM2 as key replicative stress resistor in the context of neuroblastoma 26 , we aimed in this study to functionally evaluate the role of PHF6 in this tumor entity.…”

Transcription Factors as Novel Therapeutic Targets and Drivers of Prostate Cancer Progression

“…Estrogen related receptor alpha (ERRα) is involved in the regulation of prostate energy homeostasis ( 11 ). It has been shown that ERRα can interact with hypoxia inducible factor 1 (HIF) transcription factor complex to prevent HIF-1α from undergoing proteasomal degradation and augments the cellular adaptive response to hypoxia generated by the prostate tumour cells ( 94 , 95 ). As a result, interference of this indispensable PPI is a lucrative approach to develop prostate cancer therapeutics.…”

“…As a result, interference of this indispensable PPI is a lucrative approach to develop prostate cancer therapeutics. XCT790 is an inverse agonist of ERRα ( 94 ). It was demonstrated that administration of XCT790 attenuated ERRα-HIF-1 interactions and reduced the expressions of HIF-1 ( 95 ).…”