Intracellular kinetics of the androgen receptor shown by multimodal Image Correlation Spectroscopy (mICS)

Chiu, Charles B.; Patsch, Katherin; Cutrale, Francesco; Soundararajan, Anjana; Agus, David B.; Fraser, Scott E.; Ruderman, Daniel

doi:10.1038/srep22435

Cited by 8 publications

(4 citation statements)

References 58 publications

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“…DHT-bound AR interacts with heat shock protein 27 (HSP27). When phosphorylated HSP27 is bound with AR, it translocates into the nucleus [ 28 , 29 ]. Therefore, we assumed that C3A would inhibit AR nuclear translocation by affecting the interaction between AR and HSP27.…”

Section: Resultsmentioning

confidence: 99%

Cyanidin 3-O-arabinoside suppresses DHT-induced dermal papilla cell senescence by modulating p38-dependent ER-mitochondria contacts

et al. 2022

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Background Androgenetic alopecia (AGA) is a genetic disorder caused by dihydrotestosterone (DHT), accompanied by the senescence of androgen-sensitive dermal papilla cells (DPCs) located in the base of hair follicles. DHT causes DPC senescence in AGA through mitochondrial dysfunction. However, the mechanism of this pathogenesis remains unknown. In this study, we investigated the protective role of cyanidins on DHT-induced mitochondrial dysfunction and DPC senescence and the regulatory mechanism involved. Methods DPCs were used to investigate the effect of DHT on mitochondrial dysfunction with MitoSOX and Rhod-2 staining. Senescence-associated β-galactosidase activity assay was performed to examine the involvement of membrane AR-mediated signaling in DHT-induced DPC senescence. AGA mice model was used to study the cyanidins on DHT-induced hair growth deceleration. Results Cyanidin 3-O-arabinoside (C3A) effectively decreased DHT-induced mtROS accumulation in DPCs, and C3A reversed the DHT-induced DPC senescence. Excessive mitochondrial calcium accumulation was blocked by C3A. C3A inhibited p38-mediated voltage-dependent anion channel 1 (VDAC1) expression that contributes to mitochondria-associated ER membrane (MAM) formation and transfer of calcium via VDAC1–IP3R1 interactions. DHT-induced MAM formation resulted in increase of DPC senescence. In AGA mice models, C3A restored DHT-induced hair growth deceleration, which activated hair follicle stem cell proliferation. Conclusions C3A is a promising natural compound for AGA treatments against DHT-induced DPC senescence through reduction of MAM formation and mitochondrial dysfunction.

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Section: Resultsmentioning

confidence: 99%

Cyanidin 3-O-arabinoside suppresses DHT-induced dermal papilla cell senescence by modulating p38-dependent ER-mitochondria contacts

et al. 2022

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“…Androgens are mainly known to exert genomic effects via nuclear receptors. This classical mode of action is relatively slow, since translocation of bound androgen receptors from the cytoplasm to the nucleus takes ∼20 min (Chiu et al, 2016) and subsequent genomic effects have been reported within 1 h (Jones et al, 2003). This contrasts with the "rapid response" in which testosterone activates membrane bound receptors that trigger second messenger signaling ultimately regulating membrane-bound ion channels (Rosner, 1999).…”

Section: The Time Domains Of Androgen Signalingmentioning

confidence: 99%

Testosterone Supplementation Induces Age-Dependent Augmentation of the Hypoxic Ventilatory Response in Male Rats With Contributions From the Carotid Bodies

et al. 2021

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Excessive carotid body responsiveness to O2 and/or CO2/H+ stimuli contributes to respiratory instability and apneas during sleep. In hypogonadal men, testosterone supplementation may increase the risk of sleep-disordered breathing; however, the site of action is unknown. The present study tested the hypothesis that testosterone supplementation potentiates carotid body responsiveness to hypoxia in adult male rats. Because testosterone levels decline with age, we also determined whether these effects were age-dependent. In situ hybridization determined that androgen receptor mRNA was present in the carotid bodies and caudal nucleus of the solitary tract of adult (69 days old) and aging (193–206 days old) male rats. In urethane-anesthetized rats injected with testosterone propionate (2 mg/kg; i.p.), peak breathing frequency measured during hypoxia (FiO2 = 0.12) was 11% greater vs. the vehicle treatment group. Interestingly, response intensity following testosterone treatment was positively correlated with animal age. Exposing ex vivo carotid body preparations from young and aging rats to testosterone (5 nM, free testosterone) 90–120 min prior to testing showed that the carotid sinus nerve firing rate during hypoxia (5% CO2 + 95% N2; 15 min) was augmented in both age groups as compared to vehicle (<0.001% DMSO). Ventilatory measurements performed using whole body plethysmography revealed that testosterone supplementation (2 mg/kg; i.p.) 2 h prior reduced apnea frequency during sleep. We conclude that in healthy rats, age-dependent potentiation of the carotid body’s response to hypoxia by acute testosterone supplementation does not favor the occurrence of apneas but rather appears to stabilize breathing during sleep.

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“…Androgen receptor (AR) activation involves a cascade of events, including binding to the AR-ligand binding domain (AR-LBD) in the cytoplasm, nuclear translocation, and transactivation “hyperspeckling,” where interaction with androgen response elements (AREs) regulates gene expression. These discrete steps can be measured via fluorescence polarization ( 2 ), confocal microscopy ( 3 ), and ARE-luciferase assays ( 4 ).…”

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confidence: 99%

Paradoxical androgen receptor regulation by small molecule enantiomers

Patsch

Liu

Zapotoczny

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Small molecules that target the androgen receptor (AR) are the mainstay of therapy for lethal castration-resistant prostate cancer (CRPC), yet existing drugs lose their efficacy during continued treatment. This evolution of resistance is due to heterogenous mechanisms which include AR mutations causing the identical drug to activate instead of inhibit the receptor. Understanding in molecular detail the paradoxical phenomenon wherein an AR antagonist is transformed into an agonist by structural mutations in the target receptor is thus of paramount importance. Herein, we describe a reciprocal paradox: opposing antagonist and agonist AR regulation determined uniquely by enantiomeric forms of the same drug structure. The antiandrogen BMS-641988, which has (R)-chirality at C-5 encompasses a previously uncharacterized (S)-stereoisomer that is, surprisingly, a potent agonist of AR, as demonstrated by transcriptional assays supported by cell imaging studies. This duality was reproduced in a series of novel compounds derived from the BMS-641988 scaffold. Coupled with in silico modeling studies, the results inform an AR model that explains the switch from potent antagonist to high-affinity agonist in terms of C-5 substituent steric interactions with helix 12 of the ligand binding site. They imply strategies to overcome AR drug resistance and demonstrate that insufficient enantiopurity in this class of AR antagonist can confound efforts to correlate structure with function.

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Intracellular kinetics of the androgen receptor shown by multimodal Image Correlation Spectroscopy (mICS)

Cited by 8 publications

References 58 publications

Cyanidin 3-O-arabinoside suppresses DHT-induced dermal papilla cell senescence by modulating p38-dependent ER-mitochondria contacts

Cyanidin 3-O-arabinoside suppresses DHT-induced dermal papilla cell senescence by modulating p38-dependent ER-mitochondria contacts

Testosterone Supplementation Induces Age-Dependent Augmentation of the Hypoxic Ventilatory Response in Male Rats With Contributions From the Carotid Bodies

Paradoxical androgen receptor regulation by small molecule enantiomers

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