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Melatonin inhibits lipid accumulation to repress prostate cancer progression by mediating the epigenetic modification of CES1
BACKGROUND: Androgen deprivation therapy (ADT) is the main clinical treatment for patients with advanced prostate cancer (PCa). However, PCa eventually progresses to castration‐resistant prostate cancer (CRPC), largely because of androgen receptor variation and increased intratumoral androgen synthe...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181204/ https://www.ncbi.nlm.nih.gov/pubmed/34185414 http://dx.doi.org/10.1002/ctm2.449 |
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author | Zhou, Lijie Zhang, Cai Yang, Xiong Liu, Lilong Hu, Junyi Hou, Yaxin Tao, Hong Sugimura, Haruhiko Chen, Zhaohui Wang, Liang Chen, Ke |
author_facet | Zhou, Lijie Zhang, Cai Yang, Xiong Liu, Lilong Hu, Junyi Hou, Yaxin Tao, Hong Sugimura, Haruhiko Chen, Zhaohui Wang, Liang Chen, Ke |
author_sort | Zhou, Lijie |
collection | PubMed |
description | BACKGROUND: Androgen deprivation therapy (ADT) is the main clinical treatment for patients with advanced prostate cancer (PCa). However, PCa eventually progresses to castration‐resistant prostate cancer (CRPC), largely because of androgen receptor variation and increased intratumoral androgen synthesis. Several studies have reported that one abnormal lipid accumulation is significantly related to the development of PCa. Melatonin (MLT) is a functionally pleiotropic indoleamine molecule and a key regulator of energy metabolism. The aim of our study is finding the links between CRPC and MLT and providing the basis for MLT treatment for CRPC. METHODS: We used animal CRPC models with a circadian rhythm disorder, and PCa cell lines to assess the role of melatonin in PCa. RESULTS: We demonstrated that MLT treatment inhibited tumor growth and reversed enzalutamide resistance in animal CRPC models with a circadian rhythm disorder. A systematic review and meta‐analysis demonstrated that MLT is positively associated with an increased risk of developing advanced PCa. Restoration of carboxylesterase 1 (CES1) expression by MLT treatment significantly reduced lipid droplet (LD) accumulation, thereby inducing apoptosis by increasing endoplasmic reticulum stress, reducing de novo intratumoral androgen synthesis, repressing CRPC progression and reversing the resistance to new endocrine therapy. Mechanistic investigations demonstrated that MLT regulates the epigenetic modification of CES1. Ces1‐knockout (Ces(−/−)) mice verified the important role of endogenous Ces1 in PCa. CONCLUSIONS: Our findings provide novel preclinical and clinical information about the role of melatonin in advanced PCa and characterize the importance of enzalutamide combined with MLT administration as a therapy for advanced PCa. |
format | Online Article Text |
id | pubmed-8181204 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-81812042021-06-16 Melatonin inhibits lipid accumulation to repress prostate cancer progression by mediating the epigenetic modification of CES1 Zhou, Lijie Zhang, Cai Yang, Xiong Liu, Lilong Hu, Junyi Hou, Yaxin Tao, Hong Sugimura, Haruhiko Chen, Zhaohui Wang, Liang Chen, Ke Clin Transl Med Research Articles BACKGROUND: Androgen deprivation therapy (ADT) is the main clinical treatment for patients with advanced prostate cancer (PCa). However, PCa eventually progresses to castration‐resistant prostate cancer (CRPC), largely because of androgen receptor variation and increased intratumoral androgen synthesis. Several studies have reported that one abnormal lipid accumulation is significantly related to the development of PCa. Melatonin (MLT) is a functionally pleiotropic indoleamine molecule and a key regulator of energy metabolism. The aim of our study is finding the links between CRPC and MLT and providing the basis for MLT treatment for CRPC. METHODS: We used animal CRPC models with a circadian rhythm disorder, and PCa cell lines to assess the role of melatonin in PCa. RESULTS: We demonstrated that MLT treatment inhibited tumor growth and reversed enzalutamide resistance in animal CRPC models with a circadian rhythm disorder. A systematic review and meta‐analysis demonstrated that MLT is positively associated with an increased risk of developing advanced PCa. Restoration of carboxylesterase 1 (CES1) expression by MLT treatment significantly reduced lipid droplet (LD) accumulation, thereby inducing apoptosis by increasing endoplasmic reticulum stress, reducing de novo intratumoral androgen synthesis, repressing CRPC progression and reversing the resistance to new endocrine therapy. Mechanistic investigations demonstrated that MLT regulates the epigenetic modification of CES1. Ces1‐knockout (Ces(−/−)) mice verified the important role of endogenous Ces1 in PCa. CONCLUSIONS: Our findings provide novel preclinical and clinical information about the role of melatonin in advanced PCa and characterize the importance of enzalutamide combined with MLT administration as a therapy for advanced PCa. John Wiley and Sons Inc. 2021-06-06 /pmc/articles/PMC8181204/ /pubmed/34185414 http://dx.doi.org/10.1002/ctm2.449 Text en © 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Zhou, Lijie Zhang, Cai Yang, Xiong Liu, Lilong Hu, Junyi Hou, Yaxin Tao, Hong Sugimura, Haruhiko Chen, Zhaohui Wang, Liang Chen, Ke Melatonin inhibits lipid accumulation to repress prostate cancer progression by mediating the epigenetic modification of CES1 |
title | Melatonin inhibits lipid accumulation to repress prostate cancer progression by mediating the epigenetic modification of CES1 |
title_full | Melatonin inhibits lipid accumulation to repress prostate cancer progression by mediating the epigenetic modification of CES1 |
title_fullStr | Melatonin inhibits lipid accumulation to repress prostate cancer progression by mediating the epigenetic modification of CES1 |
title_full_unstemmed | Melatonin inhibits lipid accumulation to repress prostate cancer progression by mediating the epigenetic modification of CES1 |
title_short | Melatonin inhibits lipid accumulation to repress prostate cancer progression by mediating the epigenetic modification of CES1 |
title_sort | melatonin inhibits lipid accumulation to repress prostate cancer progression by mediating the epigenetic modification of ces1 |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181204/ https://www.ncbi.nlm.nih.gov/pubmed/34185414 http://dx.doi.org/10.1002/ctm2.449 |
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