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Overview on the complexity of androgen receptor-targeted therapy for prostate cancer.

Farooqi AA, Sarkar FH - Cancer Cell Int. (2015)

Bottom Line: Therefore, newer agents must be discovered especially because newer ADT such as abiraterone and enzalutamide are becoming ineffective due to rapid development of resistance to these agents.Reconceptualization of phenotype- and genotype-driven studies have convincingly revealed that drug induced resistance is a major stumbling block in standardization of therapy.Therefore, we summarize succinctly the knowledge of drug resistance especially to ADT and potential avenues to overcome such resistance for improving the treatment outcome of PCa patients.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Translational Oncology and Personalized Medicine, Rashid Latif Medical College, 35 Km Ferozepur Road, Lahore, Pakistan.

ABSTRACT
In the past decades, the field of prostate cancer (PCa) biology has developed exponentially and paralleled with that has been the growing interest in translation of laboratory findings into clinical practice. Based on overwhelming evidence of high impact research findings which support the underlying cause of insufficient drug efficacy in patients progressing on standard androgen deprivation therapy (ADT) is due to persistent activation of the androgen receptor (AR) signaling axis. Therefore, newer agents must be discovered especially because newer ADT such as abiraterone and enzalutamide are becoming ineffective due to rapid development of resistance to these agents. High-throughput technologies are generating massive and highly dimensional genetic variation data that has helped in developing a better understanding of the dynamic repertoire of AR and AR variants. Full length AR protein and its variants modulate a sophisticated regulatory system to orchestrate cellular responses. We partition this multicomponent review into subsections addressing the underlying mechanisms of resistance to recent therapeutics, positive and negative regulators of AR signaling cascade, and how SUMOylation modulates AR induced transcriptional activity. Experimentally verified findings obtained from cell culture and preclinical studies focusing on the potential of natural agents in inhibiting mRNA/protein levels of AR, nuclear accumulation and enhanced nuclear export of AR are also discussed. We also provide spotlight on molecular basis of enzalutamide resistance with an overview of the strategies opted to overcome such resistance. AR variants are comprehensively described and different mechanisms that regulate AR variant expression are also discussed. Reconceptualization of phenotype- and genotype-driven studies have convincingly revealed that drug induced resistance is a major stumbling block in standardization of therapy. Therefore, we summarize succinctly the knowledge of drug resistance especially to ADT and potential avenues to overcome such resistance for improving the treatment outcome of PCa patients.

No MeSH data available.


Related in: MedlinePlus

Showing inactive and active states. a) Co-repressors and HDAC are recruited in the absence of AR. b) AR induced positioning of co-activators, Histone Acetyltransferases. c) SET8 a histone Methytransferase co-exists with AR.
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Fig1: Showing inactive and active states. a) Co-repressors and HDAC are recruited in the absence of AR. b) AR induced positioning of co-activators, Histone Acetyltransferases. c) SET8 a histone Methytransferase co-exists with AR.

Mentions: Substantial information has been added into the landscape of co-activator/co-repressor complexes associated with AR (FigureĀ 1), and it is now known that AR interacted with phosphorylated heterogeneous nuclear ribonucleoprotein K (hnRNP K) in nuclear matrix region in PCa cells. However, astonishingly, bicalutamide treatment reduced phosphorylated hnRNP K levels and induced its dissociation from AR [5]. Nuclear accumulation of AR is notably reduced by HepaCAM in PCa cells [6]. SPOP E3 ubiquitin ligase has been shown to degrade full-length AR by recognizing a Ser/Thr-rich degron in its hinge domain [7].Figure 1


Overview on the complexity of androgen receptor-targeted therapy for prostate cancer.

Farooqi AA, Sarkar FH - Cancer Cell Int. (2015)

Showing inactive and active states. a) Co-repressors and HDAC are recruited in the absence of AR. b) AR induced positioning of co-activators, Histone Acetyltransferases. c) SET8 a histone Methytransferase co-exists with AR.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4336517&req=5

Fig1: Showing inactive and active states. a) Co-repressors and HDAC are recruited in the absence of AR. b) AR induced positioning of co-activators, Histone Acetyltransferases. c) SET8 a histone Methytransferase co-exists with AR.
Mentions: Substantial information has been added into the landscape of co-activator/co-repressor complexes associated with AR (FigureĀ 1), and it is now known that AR interacted with phosphorylated heterogeneous nuclear ribonucleoprotein K (hnRNP K) in nuclear matrix region in PCa cells. However, astonishingly, bicalutamide treatment reduced phosphorylated hnRNP K levels and induced its dissociation from AR [5]. Nuclear accumulation of AR is notably reduced by HepaCAM in PCa cells [6]. SPOP E3 ubiquitin ligase has been shown to degrade full-length AR by recognizing a Ser/Thr-rich degron in its hinge domain [7].Figure 1

Bottom Line: Therefore, newer agents must be discovered especially because newer ADT such as abiraterone and enzalutamide are becoming ineffective due to rapid development of resistance to these agents.Reconceptualization of phenotype- and genotype-driven studies have convincingly revealed that drug induced resistance is a major stumbling block in standardization of therapy.Therefore, we summarize succinctly the knowledge of drug resistance especially to ADT and potential avenues to overcome such resistance for improving the treatment outcome of PCa patients.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Translational Oncology and Personalized Medicine, Rashid Latif Medical College, 35 Km Ferozepur Road, Lahore, Pakistan.

ABSTRACT
In the past decades, the field of prostate cancer (PCa) biology has developed exponentially and paralleled with that has been the growing interest in translation of laboratory findings into clinical practice. Based on overwhelming evidence of high impact research findings which support the underlying cause of insufficient drug efficacy in patients progressing on standard androgen deprivation therapy (ADT) is due to persistent activation of the androgen receptor (AR) signaling axis. Therefore, newer agents must be discovered especially because newer ADT such as abiraterone and enzalutamide are becoming ineffective due to rapid development of resistance to these agents. High-throughput technologies are generating massive and highly dimensional genetic variation data that has helped in developing a better understanding of the dynamic repertoire of AR and AR variants. Full length AR protein and its variants modulate a sophisticated regulatory system to orchestrate cellular responses. We partition this multicomponent review into subsections addressing the underlying mechanisms of resistance to recent therapeutics, positive and negative regulators of AR signaling cascade, and how SUMOylation modulates AR induced transcriptional activity. Experimentally verified findings obtained from cell culture and preclinical studies focusing on the potential of natural agents in inhibiting mRNA/protein levels of AR, nuclear accumulation and enhanced nuclear export of AR are also discussed. We also provide spotlight on molecular basis of enzalutamide resistance with an overview of the strategies opted to overcome such resistance. AR variants are comprehensively described and different mechanisms that regulate AR variant expression are also discussed. Reconceptualization of phenotype- and genotype-driven studies have convincingly revealed that drug induced resistance is a major stumbling block in standardization of therapy. Therefore, we summarize succinctly the knowledge of drug resistance especially to ADT and potential avenues to overcome such resistance for improving the treatment outcome of PCa patients.

No MeSH data available.


Related in: MedlinePlus