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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

Natural and synthetic agents mediated targeting of AR. a) SUMOylated AR mediated transcriptional activity activity is reduced. b-c) SENP-1 is a target of AR that deconjugated SUMO from AR thus enhancing AR mediated transcriptional activity. d) Natural and synthetic agents have shown potent inhibitory effects on SENP-1. e) AZD3514 inhibited nuclear accumulation of AR. f) Mahanine promoted nuclear export of AR. g) Urolithins and Curcumin have shown to reduce AR induced transcriptional activity. h) Natural agents also decrease mRNA and protein levels of AR.
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Fig2: Natural and synthetic agents mediated targeting of AR. a) SUMOylated AR mediated transcriptional activity activity is reduced. b-c) SENP-1 is a target of AR that deconjugated SUMO from AR thus enhancing AR mediated transcriptional activity. d) Natural and synthetic agents have shown potent inhibitory effects on SENP-1. e) AZD3514 inhibited nuclear accumulation of AR. f) Mahanine promoted nuclear export of AR. g) Urolithins and Curcumin have shown to reduce AR induced transcriptional activity. h) Natural agents also decrease mRNA and protein levels of AR.

Mentions: It has previously been convincingly revealed that N-terminal transactivation domain of AR undergoes covalent modification by SUMOs at two conserved lysine that may influence AR efficiency in stimulating expression of target genes. Increasingly it is being realized that SUMOylated AR shows a lower transcriptional activity (Figure 2). It is noteworthy that PC-3 cells stably expressing doubly SUMOylation site-mutated AR displayed a higher apoptotic rate [14,15]. 15-deoxy-Δ(12,14)-prostaglandin J(2) is also reported to trigger SUMOylation of AR [16]. In accordance with significant roleplay of SUMOylation, it has also been reported that mutation of the FOXA1 SUMOylation sites considerably reduced AR nuclear mobility. Forkhead box (FOX) protein A1 is involved in chromatin remodelling and facilitates AR positioning at DNA [14,15]. Gly residue is present at 524th position downstream to the core of the second synergy control motif in AR. AR bearing the G524D substitution displayed a higher transcriptional activity than wild type AR. Moreover, SUMOylation-deficient AR mutant (K386R/K520R), also induced significant target gene expression [17]. Heat stress resulted in generation of prominent intranuclear granules that contained SUMO-2/3 and AR. Stress induced SUMOylated AR transportation towards nuclear matrix. Quantitative chromatin immunoprecipitation (qChIP) assay has provided clear evidence of detachment of androgen-loaded AR from regulatory regions of these genes in Heat stressed prostate cancer cells. Using anti-SUMO-2/3 antibody, it was shown that heat stressed prostate cancer cells showed accumulation of SUMO-2/3 in the AR-binding regions of the target genes [18]. Rapidly emerging experimental findings are also providing new information regarding positive regulators of AR induced signaling. SUMO-specific protease 1 (SENP1) has previously been identified as an AR regulated gene and reportedly decreased SUMOylation of AR via deconjugation of AR-SUMO covalent bond [19] (Figure 2). Triptolide, isolated from Tripterygium wilfordii Hook notably inhibited SENP1 that consequently resulted in a markedly reduced SUMOylated AR induced transcriptional activity [20]. Benzodiazepine-based inhibitors and 2-(4-Chlorophenyl)-2-oxoethyl 4-benzamidobenzoate derivatives have shown potential in targeting of SENP1 [21,22] (Figure 2). These recent reports suggest that newer arsenals are beginning to emerge for AR-targeted therapeutics which could be useful in improving the therapeutic outcome of PCa patients especially for patients with CRPC and/or mCRPC.Figure 2


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

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

Natural and synthetic agents mediated targeting of AR. a) SUMOylated AR mediated transcriptional activity activity is reduced. b-c) SENP-1 is a target of AR that deconjugated SUMO from AR thus enhancing AR mediated transcriptional activity. d) Natural and synthetic agents have shown potent inhibitory effects on SENP-1. e) AZD3514 inhibited nuclear accumulation of AR. f) Mahanine promoted nuclear export of AR. g) Urolithins and Curcumin have shown to reduce AR induced transcriptional activity. h) Natural agents also decrease mRNA and protein levels of AR.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Natural and synthetic agents mediated targeting of AR. a) SUMOylated AR mediated transcriptional activity activity is reduced. b-c) SENP-1 is a target of AR that deconjugated SUMO from AR thus enhancing AR mediated transcriptional activity. d) Natural and synthetic agents have shown potent inhibitory effects on SENP-1. e) AZD3514 inhibited nuclear accumulation of AR. f) Mahanine promoted nuclear export of AR. g) Urolithins and Curcumin have shown to reduce AR induced transcriptional activity. h) Natural agents also decrease mRNA and protein levels of AR.
Mentions: It has previously been convincingly revealed that N-terminal transactivation domain of AR undergoes covalent modification by SUMOs at two conserved lysine that may influence AR efficiency in stimulating expression of target genes. Increasingly it is being realized that SUMOylated AR shows a lower transcriptional activity (Figure 2). It is noteworthy that PC-3 cells stably expressing doubly SUMOylation site-mutated AR displayed a higher apoptotic rate [14,15]. 15-deoxy-Δ(12,14)-prostaglandin J(2) is also reported to trigger SUMOylation of AR [16]. In accordance with significant roleplay of SUMOylation, it has also been reported that mutation of the FOXA1 SUMOylation sites considerably reduced AR nuclear mobility. Forkhead box (FOX) protein A1 is involved in chromatin remodelling and facilitates AR positioning at DNA [14,15]. Gly residue is present at 524th position downstream to the core of the second synergy control motif in AR. AR bearing the G524D substitution displayed a higher transcriptional activity than wild type AR. Moreover, SUMOylation-deficient AR mutant (K386R/K520R), also induced significant target gene expression [17]. Heat stress resulted in generation of prominent intranuclear granules that contained SUMO-2/3 and AR. Stress induced SUMOylated AR transportation towards nuclear matrix. Quantitative chromatin immunoprecipitation (qChIP) assay has provided clear evidence of detachment of androgen-loaded AR from regulatory regions of these genes in Heat stressed prostate cancer cells. Using anti-SUMO-2/3 antibody, it was shown that heat stressed prostate cancer cells showed accumulation of SUMO-2/3 in the AR-binding regions of the target genes [18]. Rapidly emerging experimental findings are also providing new information regarding positive regulators of AR induced signaling. SUMO-specific protease 1 (SENP1) has previously been identified as an AR regulated gene and reportedly decreased SUMOylation of AR via deconjugation of AR-SUMO covalent bond [19] (Figure 2). Triptolide, isolated from Tripterygium wilfordii Hook notably inhibited SENP1 that consequently resulted in a markedly reduced SUMOylated AR induced transcriptional activity [20]. Benzodiazepine-based inhibitors and 2-(4-Chlorophenyl)-2-oxoethyl 4-benzamidobenzoate derivatives have shown potential in targeting of SENP1 [21,22] (Figure 2). These recent reports suggest that newer arsenals are beginning to emerge for AR-targeted therapeutics which could be useful in improving the therapeutic outcome of PCa patients especially for patients with CRPC and/or mCRPC.Figure 2

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