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Sympathetic signaling facilitates progression of neuroendocrine prostate cancer
The progression of prostate cancer (PC) into neuroendocrine prostate cancer (NEPC) is a major challenge in treating PC. In NEPC, the PC cells undergo neuroendocrine differentiation (NED); however, the exact molecular mechanism that triggers NED is unknown. Peripheral nerves are recently shown to pro...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8608828/ https://www.ncbi.nlm.nih.gov/pubmed/34811362 http://dx.doi.org/10.1038/s41420-021-00752-1 |
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author | Dwivedi, Shubham Bautista, Maricris Shrestha, Sanskriti Elhasasna, Hussain Chaphekar, Tanaya Vizeacoumar, Frederick S. Krishnan, Anand |
author_facet | Dwivedi, Shubham Bautista, Maricris Shrestha, Sanskriti Elhasasna, Hussain Chaphekar, Tanaya Vizeacoumar, Frederick S. Krishnan, Anand |
author_sort | Dwivedi, Shubham |
collection | PubMed |
description | The progression of prostate cancer (PC) into neuroendocrine prostate cancer (NEPC) is a major challenge in treating PC. In NEPC, the PC cells undergo neuroendocrine differentiation (NED); however, the exact molecular mechanism that triggers NED is unknown. Peripheral nerves are recently shown to promote PC. However, their contribution to NEPC was not studied well. In this study, we explored whether sympathetic neurosignaling contributes to NED. We found that human prostate tumors from patients that later developed metastases and castration-resistant prostate cancer (CRPC), a stage preceding to NEPC, have high sympathetic innervations. Our work revealed that high concentrations of the sympathetic neurotransmitter norepinephrine (NE) induces NED-like changes in PC cells in vitro, evident by their characteristic cellular and molecular changes. The NE-mediated NED was effectively inhibited by the Adrβ2 blocker propranolol. Strikingly, propranolol along with castration also significantly inhibited the development and progression of NEPC in vivo in an orthotopic NEPC model. Altogether, our results indicate that the NE-Adrβ2 axis is a potential therapeutic intervention point for NEPC. |
format | Online Article Text |
id | pubmed-8608828 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-86088282021-12-15 Sympathetic signaling facilitates progression of neuroendocrine prostate cancer Dwivedi, Shubham Bautista, Maricris Shrestha, Sanskriti Elhasasna, Hussain Chaphekar, Tanaya Vizeacoumar, Frederick S. Krishnan, Anand Cell Death Discov Article The progression of prostate cancer (PC) into neuroendocrine prostate cancer (NEPC) is a major challenge in treating PC. In NEPC, the PC cells undergo neuroendocrine differentiation (NED); however, the exact molecular mechanism that triggers NED is unknown. Peripheral nerves are recently shown to promote PC. However, their contribution to NEPC was not studied well. In this study, we explored whether sympathetic neurosignaling contributes to NED. We found that human prostate tumors from patients that later developed metastases and castration-resistant prostate cancer (CRPC), a stage preceding to NEPC, have high sympathetic innervations. Our work revealed that high concentrations of the sympathetic neurotransmitter norepinephrine (NE) induces NED-like changes in PC cells in vitro, evident by their characteristic cellular and molecular changes. The NE-mediated NED was effectively inhibited by the Adrβ2 blocker propranolol. Strikingly, propranolol along with castration also significantly inhibited the development and progression of NEPC in vivo in an orthotopic NEPC model. Altogether, our results indicate that the NE-Adrβ2 axis is a potential therapeutic intervention point for NEPC. Nature Publishing Group UK 2021-11-22 /pmc/articles/PMC8608828/ /pubmed/34811362 http://dx.doi.org/10.1038/s41420-021-00752-1 Text en © Crown 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Dwivedi, Shubham Bautista, Maricris Shrestha, Sanskriti Elhasasna, Hussain Chaphekar, Tanaya Vizeacoumar, Frederick S. Krishnan, Anand Sympathetic signaling facilitates progression of neuroendocrine prostate cancer |
title | Sympathetic signaling facilitates progression of neuroendocrine prostate cancer |
title_full | Sympathetic signaling facilitates progression of neuroendocrine prostate cancer |
title_fullStr | Sympathetic signaling facilitates progression of neuroendocrine prostate cancer |
title_full_unstemmed | Sympathetic signaling facilitates progression of neuroendocrine prostate cancer |
title_short | Sympathetic signaling facilitates progression of neuroendocrine prostate cancer |
title_sort | sympathetic signaling facilitates progression of neuroendocrine prostate cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8608828/ https://www.ncbi.nlm.nih.gov/pubmed/34811362 http://dx.doi.org/10.1038/s41420-021-00752-1 |
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