Androgen receptor: structure, role in prostate cancer and drug discovery

Tan, Ming; Li, Jun; Xu, H. Eric; Melcher, Karsten; Yong, Eu Leong

doi:10.1038/aps.2014.18

Cited by 663 publications

(662 citation statements)

References 200 publications

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“…However, the details of their mechanisms of action are different (reviewed in refs. 41,42). It has been proposed that bicalutamide binds an additional binding pocket (B-site) in the proximity of the androgen-binding pocket (34).…”

Section: In Silico Modelingmentioning

confidence: 99%

The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

Prekovic

Royen

Voet

et al. 2016

Molecular Cancer Therapeutics

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Treatment-induced mutations in the ligand-binding domain of the androgen receptor (AR) are known to change antagonists into agonists. Recently, the F877L mutation has been described to convert enzalutamide into an agonist. This mutation was seen to co-occur in the endogenous AR allele of LNCaP cells, next to the T878A mutation. Here, we studied the effects of enzalutamide on the F877L and T878A mutants, as well as the double-mutant AR (F877L/T878A). Molecular modeling revealed favorable structural changes in the double-mutant AR that lead to a decrease in steric clashes for enzalutamide. Ligand-binding assays confirmed that the F877L mutation leads to an increase in relative binding affinity for enzalutamide, but only the combination with the T878A mutation resulted in a strong agonistic activity. This correlated with changes in coregulator recruitment and chromatin interactions. Our data show that enzalutamide is only a very weak partial agonist of the AR F877L, and a strong partial agonist of the double-mutant AR.

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Section: In Silico Modelingmentioning

confidence: 99%

The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

Prekovic

Royen

Voet

et al. 2016

Molecular Cancer Therapeutics

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“…AR attains activation and becomes functional as a consequence of agonists binding to its receptor, or when phosphorylated by Akt or due to mutation is ensued by its nuclear translocation. In the nucleus, AR employs co-activators that facilitate its binding to the promoter sequence of responsive genes to activate their expression [29]. Inhibition of Hsp90 destabilizes both wild type and mutant AR, presumably by releasing AR from the chaperone complex, to be subjected to degradation by the proteasome.…”

Section: Protein Binding Partners Of Maspinmentioning

confidence: 99%

Maspin Expression and its Metastasis Suppressing Function in Prostate Cancer

Shankar¹,

Candamo²,

MacLennan³

et al. 2016

Prostate Cancer - Leading-Edge Diagnostic Procedures and Treatments

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Mammary Serine Protease Inhibitor (Maspin) is a unique member of the serpin family with tumor suppressive properties. Maspin is a secreted protein encoded by a class II tumor suppressor gene, expressed in normal prostate luminal and basal cells but reduced or absent in prostate cancer. Currently, there is a consensus that maspin expression in prostate cancer is an indicator of a better prognosis and is a predictive marker for therapeutic response in prostate cancer. Experimental evidence consistently indicates that maspin suppresses tumor growth, invasion, and metastasis and promotes apoptosis in cancer cells. In this chapter, we discuss regulation of maspin expression, binding partners of maspin, and pathways through which maspin exerts its tumor suppressive properties. In addition, we summarize the progress that investigators have made in clarifying the role of maspin in prostate cancer biology and in assessing its role as a diagnostic marker and therapeutic agent.

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“…Androgen receptor (AR) and its downstream signaling play a crucial role in the normal development and function of the prostate 2,3 . AR is a DNA-binding transcription factor governing the development and maintenance of the male sexual phenotype.…”

Section: Introductionmentioning

confidence: 99%

“…Abnormal function of the AR has been proposed to be one of the main reasons for the progression of human prostate cancer 5,6 . Decrease in AR activity through androgen suppression is one of the hormonal treatment strategies for prostate cancer 3,7 . Post-translational modifications of the AR by phosphorylation, sumoylation, and acetylation direct its subcellular localization, association with co-activators or co-repressors, and DNA binding ability [8][9][10] .…”

Section: Introductionmentioning

confidence: 99%