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Glucocorticoid Receptor and β-Catenin Interact in Prostate Cancer Cells and Their Co-Inhibition Attenuates Tumorsphere Formation, Stemness, and Docetaxel Resistance

Therapy resistance hinders the efficacy of anti-androgen therapies and taxane-based chemotherapy for advanced prostate cancer (PCa). Glucocorticoid receptor (GR) signaling mediates resistance to androgen receptor signaling inhibitors (ARSI) and has also been recently implicated in PCa resistance to...

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Autores principales: Martinez, Shannalee R., Elix, Catherine C., Ochoa, Pedro T., Sanchez-Hernandez, Evelyn S., Alkashgari, Hossam R., Ortiz-Hernandez, Greisha L., Zhang, Lubo, Casiano, Carlos A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10139020/
https://www.ncbi.nlm.nih.gov/pubmed/37108293
http://dx.doi.org/10.3390/ijms24087130
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author Martinez, Shannalee R.
Elix, Catherine C.
Ochoa, Pedro T.
Sanchez-Hernandez, Evelyn S.
Alkashgari, Hossam R.
Ortiz-Hernandez, Greisha L.
Zhang, Lubo
Casiano, Carlos A.
author_facet Martinez, Shannalee R.
Elix, Catherine C.
Ochoa, Pedro T.
Sanchez-Hernandez, Evelyn S.
Alkashgari, Hossam R.
Ortiz-Hernandez, Greisha L.
Zhang, Lubo
Casiano, Carlos A.
author_sort Martinez, Shannalee R.
collection PubMed
description Therapy resistance hinders the efficacy of anti-androgen therapies and taxane-based chemotherapy for advanced prostate cancer (PCa). Glucocorticoid receptor (GR) signaling mediates resistance to androgen receptor signaling inhibitors (ARSI) and has also been recently implicated in PCa resistance to docetaxel (DTX), suggesting a role in therapy cross-resistance. Like GR, β-catenin is upregulated in metastatic and therapy-resistant tumors and is a crucial regulator of cancer stemness and ARSI resistance. β-catenin interacts with AR to promote PCa progression. Given the structural and functional similarities between AR and GR, we hypothesized that β-catenin also interacts with GR to influence PCa stemness and chemoresistance. As expected, we observed that treatment with the glucocorticoid dexamethasone promotednuclear accumulation of GR and active β-catenin in PCa cells. Co-immunoprecipitation studies showed that GR and β-catenin interact in DTX-resistant and DTX-sensitive PCa cells. Pharmacological co-inhibition of GR and β-catenin, using the GR modulator CORT-108297 and the selective β-catenin inhibitor MSAB, enhanced cytotoxicity in DTX-resistant PCa cells grown in adherent and spheroid cultures and decreased CD44+/CD24– cell populations in tumorspheres. These results indicate that GR and β-catenin influence cell survival, stemness, and tumorsphere formation in DTX-resistant cells. Their co-inhibition could be a promising therapeutic strategy to overcome PCa therapy cross-resistance.
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spelling pubmed-101390202023-04-28 Glucocorticoid Receptor and β-Catenin Interact in Prostate Cancer Cells and Their Co-Inhibition Attenuates Tumorsphere Formation, Stemness, and Docetaxel Resistance Martinez, Shannalee R. Elix, Catherine C. Ochoa, Pedro T. Sanchez-Hernandez, Evelyn S. Alkashgari, Hossam R. Ortiz-Hernandez, Greisha L. Zhang, Lubo Casiano, Carlos A. Int J Mol Sci Article Therapy resistance hinders the efficacy of anti-androgen therapies and taxane-based chemotherapy for advanced prostate cancer (PCa). Glucocorticoid receptor (GR) signaling mediates resistance to androgen receptor signaling inhibitors (ARSI) and has also been recently implicated in PCa resistance to docetaxel (DTX), suggesting a role in therapy cross-resistance. Like GR, β-catenin is upregulated in metastatic and therapy-resistant tumors and is a crucial regulator of cancer stemness and ARSI resistance. β-catenin interacts with AR to promote PCa progression. Given the structural and functional similarities between AR and GR, we hypothesized that β-catenin also interacts with GR to influence PCa stemness and chemoresistance. As expected, we observed that treatment with the glucocorticoid dexamethasone promotednuclear accumulation of GR and active β-catenin in PCa cells. Co-immunoprecipitation studies showed that GR and β-catenin interact in DTX-resistant and DTX-sensitive PCa cells. Pharmacological co-inhibition of GR and β-catenin, using the GR modulator CORT-108297 and the selective β-catenin inhibitor MSAB, enhanced cytotoxicity in DTX-resistant PCa cells grown in adherent and spheroid cultures and decreased CD44+/CD24– cell populations in tumorspheres. These results indicate that GR and β-catenin influence cell survival, stemness, and tumorsphere formation in DTX-resistant cells. Their co-inhibition could be a promising therapeutic strategy to overcome PCa therapy cross-resistance. MDPI 2023-04-12 /pmc/articles/PMC10139020/ /pubmed/37108293 http://dx.doi.org/10.3390/ijms24087130 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Martinez, Shannalee R.
Elix, Catherine C.
Ochoa, Pedro T.
Sanchez-Hernandez, Evelyn S.
Alkashgari, Hossam R.
Ortiz-Hernandez, Greisha L.
Zhang, Lubo
Casiano, Carlos A.
Glucocorticoid Receptor and β-Catenin Interact in Prostate Cancer Cells and Their Co-Inhibition Attenuates Tumorsphere Formation, Stemness, and Docetaxel Resistance
title Glucocorticoid Receptor and β-Catenin Interact in Prostate Cancer Cells and Their Co-Inhibition Attenuates Tumorsphere Formation, Stemness, and Docetaxel Resistance
title_full Glucocorticoid Receptor and β-Catenin Interact in Prostate Cancer Cells and Their Co-Inhibition Attenuates Tumorsphere Formation, Stemness, and Docetaxel Resistance
title_fullStr Glucocorticoid Receptor and β-Catenin Interact in Prostate Cancer Cells and Their Co-Inhibition Attenuates Tumorsphere Formation, Stemness, and Docetaxel Resistance
title_full_unstemmed Glucocorticoid Receptor and β-Catenin Interact in Prostate Cancer Cells and Their Co-Inhibition Attenuates Tumorsphere Formation, Stemness, and Docetaxel Resistance
title_short Glucocorticoid Receptor and β-Catenin Interact in Prostate Cancer Cells and Their Co-Inhibition Attenuates Tumorsphere Formation, Stemness, and Docetaxel Resistance
title_sort glucocorticoid receptor and β-catenin interact in prostate cancer cells and their co-inhibition attenuates tumorsphere formation, stemness, and docetaxel resistance
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10139020/
https://www.ncbi.nlm.nih.gov/pubmed/37108293
http://dx.doi.org/10.3390/ijms24087130
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