La mutación T878A del receptor de andrógenos podría ser activada por esteroides endógenos debido a pérdida de selectividad

David De la Mora González, Fausto Rojas-Durán, Gonzalo Emiliano Aranda Abreu, Fernando Rafael Ramos-Morales, Abraham Vidal-Limón, Jorge Suárez-Medellín

Resumen


Los andrógenos son hormonas esteroideas involucradas en el crecimiento y desarrollo de la próstata actuando a través del receptor de andrógenos, un receptor nuclear que funciona como factor de transcripción dependiente de ligando del cual se conoce la estructura cristalográfica del dominio de unión a ligando. En etapas avanzadas del cáncer de próstata existen mutaciones que pueden contribuir al surgimiento de la etapa resistente a la castración, como la mutante T878A; además, hay evidencia de que a pesar del bloqueo androgénico existe activación del receptor que puede estar mediada por esteroidogénesis intratumoral y que las mutaciones en el receptor pueden hacer que se active por otros andrógenos debido a pérdida de la selectividad que conlleva a una promiscuidad de ligandos. Por lo tanto, el objetivo de este trabajo fue recopilar las estructuras químicas de andrógenos u otras hormonas esteroideas presentes en el microambiente tumoral y evaluar si la presencia de la mutante T878A afecta su afinidad por el receptor, lo cual se llevó a cabo mediante un análisis in silico de acoplamiento molecular por conglomerado para calcular cambios en la energía libre de acoplamiento de la formación del complejo ligando-receptor. Se encontró que la presencia de la mutación aumenta de manera significativa la afinidad de los ligandos dehidroepiandrosterona, androsterona, progesterona, cortisol y 17-hidroxipregnenolona, por lo que es posible que debido a la mutación el receptor esté siendo activado por esteroides endógenos, lo que no ocurría en condiciones fisiológicas.

Abstract

Androgens are steroid hormones involved in prostate growth and development via activation of the androgen receptor, a nuclear receptor and ligand-dependent transcription factor for which the crystallographic structure of the ligand-binding domain is known. Some mutations in advanced prostate cancer are known to drive the disease into a castration-resistant stage, such as the T878A mutation; furthermore, there is evidence that intratumoral steroidogenesis-me-diated androgen receptor activation exists despite androgen blockade and receptor mutations may contribute to its activation by other androgens due to a loss of selectivity leading to ligand promiscuity. Therefore, the aim of this work was to collect the chemical structures of androgens or other steroid hormones known to be present in the tumoral microenvironment and to eva-luate whether mutant T878A affects the affinity for their receptor. In order to do that, ensemble molecular docking was performed to calculate changes on the free binding energy of ligand-receptor complex formation. We found that the mutant significantly increased the affinity of some ligands such as dehydroepiandrosterone, androsterone, progesterone, cortisol and 17-hydroxypregnenolone. Thus, it is possible that this mutant receptor is being activated by endogenous steroids rather than those that activate it under physiological conditions.

Keywords: Molecular docking, androgen receptor, prostate cancer, affinity, promiscuity.

 


Palabras clave


Acoplamiento molecular; receptor de andrógenos; cáncer de próstata; afinidad; promiscuidad.

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Referencias


Selvaraj, V., Stocco, D. M., & Clark, B. J. (2018). Current knowledge on the acute regulation of steroidogenesis. In Biology of Reproduction (Vol. 99, Issue 1, pp. 13–26). Oxford University Press. https://doi.org/10.1093/biolre/ioy102

Luu-The, V., Bélanger, A., & Labrie, F. (2008). Androgen biosynthetic pathways in the human prostate. Best Practice and Research: Clinical Endocrinology and Metabolism, 22(2), 207–221. https://doi.org/10.1016/j.beem.2008.01.008

Desai, K., McManus, J. M., & Sharifi, N. (2021). Hormonal therapy for prostate cancer. Endocrine Reviews, 42(3), 354–373. https://doi.org/10.1210/endrev/bnab002

Naamneh Elzenaty, R., du Toit, T., & Flück, C. E. (2022). Basics of androgen synthesis and action. In Best Practice and Re-search: Clinical Endocrinology and Me-tabolism (Vol. 36, Issue 4). Bailliere Tin-dall Ltd. https://doi.org/10.1016/j.beem.2022.101665

Barnard, M., Mostaghel, E. A., Auchus, R. J., & Storbeck, K. H. (2020). The role of ad-renal derived androgens in castration resistant prostate cancer. Journal of Steroid Biochemistry and Molecular Bi-ology, 197. https://doi.org/10.1016/j.jsbmb.2019.105506

Tan, M. E., Li, J., Xu, H. E., Melcher, K., & Yong, E. L. (2015). Androgen receptor: Structure, role in prostate cancer and drug discovery. Acta Pharmacologica Sinica, 36(1), 3–23. https://doi.org/10.1038/aps.2014.18

Armandari, I., Hamid, A. R., Verhaegh, G., & Schalken, J. (2014). Intratumoral steroidogenesis in castration-resistant prostate cancer: a target for therapy. Prostate International, 2(3), 105–113. https://doi.org/10.12954/pi.14063

Cooper, L., & Page, S. (2014). Androgens and prostate disease. Asian Journal of Andrology, 16(2), 248. https://doi.org/10.4103/1008-682X.122361

Armstrong, C. M., & Gao, A. C. (2021). Dysregulated androgen synthesis and anti-androgen resistance in advanced prostate cancer. American Journal of Cli-nical and Experimental Urology, 9(4), 292–300. http://www.ncbi.nlm.nih.gov/pubmed/34541028

Veldscholte, J., Berrevoets, C. A., Ris-Stalpers, C., Kuiper, G. G. J. M., Jenster, G., Trapman, J., Brinkmann, A. O., & Mulder, E. (1992). The androgen receptor in LNCaP cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiandrogens. Journal of Steroid Bio-chemistry and Molecular Biology, 41(3–8), 665–669. https://doi.org/10.1016/0960-0760(92)90401-4

Liu, H. L., Zhong, H. Y., Song, T. Q., & Li, J. Z. (2017). A molecular modeling study of the hydroxyflutamide resistance mecha-nism induced by androgen receptor mu-tations. International Journal of Molecu-lar Sciences, 18(9). https://doi.org/10.3390/ijms18091823

Snaterse, G., Visser, J. A., Arlt, W., & Hofland, J. (2017). Circulating steroid hormone variations throughout differ-ent stages of prostate cancer. Endocrine-Related Cancer, 24(11), R403–R420. https://doi.org/10.1530/ERC-17-0155

Vidal-Limon, A. M., Luna-Martinez, O. D., Rojas-Durán, F., Meza-Menchaca, T., Hernández-Aguilar, M. E., Trigos, A., & Suárez-Medellín, J. (2017). Molecular Dy-namics and Virtual Screening Analysis of Lanosterol Derivatives from Ganoderma Medicinal Mushrooms (Agaricomycetes) as Selective Ligands of Human Androgen Receptor. International Journal of Medi-cinal Mushrooms, 19(7), 595–605. https://doi.org/10.1615/IntJMedMushrooms.2017021162

Deb, S., Pham, S., Ming, D. S., Chin, M. Y., Adomat, H., Hurtado-Coll, A., Gleave, M. E., & Tomlinson Guns, E. S. (2018). Char-acte-rization of precursor-dependent steroidogenesis in human prostate can-cer models. Cancers, 10(10), 1–21. https://doi.org/10.3390/cancers10100343

Hanwell, M. D., Curtis, D. E., Lonie, D. C., Vandermeersch, T., Zurek, E., & Hutchison, G. R. (2012). Avogadro: an ad-vanced semantic chemical editor, visual-ization, and analysis platform. Journal of Cheminformatics, 4(1), 17. https://doi.org/10.1186/1758-2946-4-17

The PyMOL Molecular Graphics System (Version 1.2r3pre). Schrödinger, LLC.

Case, D. A., Walker, R. C., Cheatham, T. E., Simmerling, C., Roitberg, A., Merz, K. M., Luo, R., Darden, T., Wang, J., Duke, R. E., Roe, D. R., LeGrand, S., Swails, J., Götz, A. W., Smith, J., Cerutti, D., Brozell, S. R., Lu-chko, T., Cruzeiro, V. W. D., … Kollman, P. A. (2018). Amber 18. In University of Cali-fornia, San Francisco. 2018. http://ambermd.org/doc12/Amber18.pdf

Grant, B. J., Skjærven, L., & Yao, X. Q. (2021). The Bio3D packages for structural bioinformatics. Protein Science, 30(1), 20–30. https://doi.org/10.1002/pro.3923

Trott, O., & Olson, A. J. (2009). AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithread-ing. Journal of Computational Chemistry, 31(2). https://doi.org/10.1002/jcc.21334

Stierand, K., Maaß, P. C., & Rarey, M. (2006). Molecular complexes at a glance: Automated generation of two-dimensional complex diagrams. Bioin-formatics, 22(14), 1710–1716. https://doi.org/10.1093/bioinformatics/btl150

Fox, J., & Bouchet-Valat, M. (2022). Rcmdr: R Commander. https://socialsciences.mcmaster.ca/jfox/Misc/Rcmdr/

Celik, L., Lund, J. D. D., & Schiøtt, B. (2008). Exploring interactions of endo-crine-disrupting compounds with differ-ent conformations of the human estro-gen receptor α ligand binding domain: A molecular docking study. Chemical Research in Toxicology, 21(11), 2195–2206. https://doi.org/10.1021/tx800278d

Muñoz-Fonseca, M. B., Vidal-Limon, A., Fernández-Pomares, C., Rojas-Durán, F., Hernández-Aguilar, M. E., Espinoza, C., Trigos, A., & Suárez-Medellín, J. (2021). Er-gosterol exerts a differential effect on AR-dependent LNCaP and AR-independent DU-145 cancer cells. Natural Product Research, 35(22), 4857–4860. https://doi.org/10.1080/14786419.2020.1737054

Pereira de Jésus-Tran, K., Côté, P.-L., Can-tin, L., Blanchet, J., Labrie, F., & Breton, R. (2006). Comparison of crystal structures of human androgen receptor ligand-bin-ding domain complexed with various a-gonists reveals molecular determinants responsible for binding affinity. Protein Science, 15(5), 987–999. https://doi.org/10.1110/ps.051905906

Schiffer, L., Arlt, W., & Storbeck, K. H. (2018). Intracrine androgen biosynthesis, metabolism and action revisited. In Mo-lecular and Cellular Endocrinology (Vol. 465, pp. 4–26). Elsevier Ireland Ltd. https://doi.org/10.1016/j.mce.2017.08.016

Green, S. M., Mostaghel, E. A., & Nelson, P. S. (2012). Androgen action and metabo-lism in prostate cancer. Molecular and Cellular Endocrinology, 360(1–2), 3–13. https://doi.org/10.1016/j.mce.2011.09.046

Zhao, X. Y., Malloy, P. J., Krishnan, A. V., Swami, S., Navone, N. M., Peehl, D. M., & Feldman, D. (2000). Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mu-tated androgen receptor. Nature Medi-cine, 6(6), 703–706. https://doi.org/10.1038/76287

Feng, Q., & He, B. (2019). Androgen Recep-tor Signaling in the Development of Cas-tration-Resistant Prostate Cancer. Frontiers in Oncology, 9. https://doi.org/10.3389/fonc.2019.00858.




DOI: https://doi.org/10.25009/eb.v14i35.2622

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