A Systematic Comparison of Antiandrogens Identifies Androgen Receptor Protein Stability as an Indicator for Treatment Response

Autor:	Robert Seed, Holger H.H. Erb, Celina Ebersbach, Tiziana Siciliano, Cem Aksoy, Christian Thomas, Alicia-Marie K. Beier, Matthias B Stope, Ingo H. Simons
Rok vydání:	2021
Předmět:	AR signaling Bicalutamide therapy resistance medicine.drug_class Antiandrogens Science Antiandrogen urologic and male genital diseases General Biochemistry Genetics and Molecular Biology Article chemistry.chemical_compound LNCaP medicine Enzalutamide nuclear receptor Antiandrogen Therapy Ecology Evolution Behavior and Systematics proteasomes Chemistry Apalutamide Paleontology prostate cancer Darolutamide Space and Planetary Science Cancer research hormones hormone substitutes and hormone antagonists medicine.drug
Zdroj:	Life Volume 11 Issue 9 Life, Vol 11, Iss 874, p 874 (2021)
ISSN:	2075-1729
Popis:	Antiandrogen therapy is a primary treatment for patients with metastasized prostate cancer. Whilst the biologic mechanisms of antiandrogens have been extensively studied, the operating protocols used for the characterization of these drugs were not identical, limiting their comparison. Here, the antiandrogens Bicalutamide, Enzalutamide, Apalutamide, and Darolutamide were systematically compared using identical experimental setups. Androgen-dependent LNCaP and LAPC4 cells as well as androgen-independent C4-2 cells were treated with distinct concentrations of antiandrogens. Androgen receptor (AR)-mediated gene transactivation was determined using qPCR. Cell viability was measured by WST1 assay. Protein stability and AR localization were determined using western blot. Response to the tested antiandrogens across cellular backgrounds differed primarily in AR-mediated gene transactivation and cell viability. Antiandrogen treatment in LNCaP and LAPC4 cells resulted in AR protein level reduction, whereas in C4-2 cells marginal decreased AR protein was observed after treatment. In addition, AR downregulation was already detectable after 4 h, whereas reduced AR-mediated gene transactivation was not observed before 6 h. None of the tested antiandrogens displayed an advantage on the tested parameters within one cell line as opposed to the cellular background, which seems to be the primary influence on antiandrogen efficacy. Moreover, the results revealed a prominent role in AR protein stability. It is one of the first events triggered by antiandrogens and correlated with antiandrogen efficiency. Therefore, AR stability may surrogate antiandrogen response and may be a possible target to reverse antiandrogen resistance.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dc8186ad5e6ec03cc3d9d9f13d96d0a0 https://pubmed.ncbi.nlm.nih.gov/34575023 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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