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Deficiency of NEIL3 Enhances the Chemotherapy Resistance of Prostate Cancer

Acquired treatment resistance is an important cause of death in prostate cancer, and this study aimed to explore the mechanisms of chemotherapy resistance in prostate cancer. We employed castration-resistant prostate cancer (CRPC), neuroendocrine prostate cancer (NEPC), and chemotherapy-resistant pr...

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Autores principales: Wang, Yiwei, Xu, Liuyue, Shi, Shanshan, Wu, Sha, Meng, Ruijie, Chen, Huifang, Jiang, Zhenyou
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071437/
https://www.ncbi.nlm.nih.gov/pubmed/33921035
http://dx.doi.org/10.3390/ijms22084098
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author Wang, Yiwei
Xu, Liuyue
Shi, Shanshan
Wu, Sha
Meng, Ruijie
Chen, Huifang
Jiang, Zhenyou
author_facet Wang, Yiwei
Xu, Liuyue
Shi, Shanshan
Wu, Sha
Meng, Ruijie
Chen, Huifang
Jiang, Zhenyou
author_sort Wang, Yiwei
collection PubMed
description Acquired treatment resistance is an important cause of death in prostate cancer, and this study aimed to explore the mechanisms of chemotherapy resistance in prostate cancer. We employed castration-resistant prostate cancer (CRPC), neuroendocrine prostate cancer (NEPC), and chemotherapy-resistant prostate cancer datasets to screen for potential target genes. The Cancer Genome Atlas (TCGA) was used to detect the correlation between the target genes and prognosis and clinical characteristics. Nei endonuclease VIII-like 3 (NEIL3) knockdown cell lines were constructed with RNA interference. Prostate cancer cells were treated with enzalutamide for the androgen deprivation therapy (ADT) model, and with docetaxel and cisplatin for the chemotherapy model. Apoptosis and the cell cycle were examined using flow cytometry. RNA sequencing and western blotting were performed in the knockdown Duke University 145 (DU145) cell line to explore the possible mechanisms. The TCGA dataset demonstrated that high NEIL3 was associated with a high T stage and Gleason score, and indicated a possibility of lymph node metastasis, but a good prognosis. The cell therapy models showed that the loss of NEIL3 could promote the chemotherapy resistance (but not ADT resistance) of prostate cancer (PCa). Flow cytometry revealed that the loss of NEIL3 in PCa could inhibit cell apoptosis and cell cycle arrest under cisplatin treatment. RNA sequencing showed that the knockdown of NEIL3 changes the expression of neuroendocrine-related genes. Further western blotting revealed that the loss of NEIL3 could significantly promote the phosphorylation of ATR serine/threonine kinase (ATR) and ATM serine/threonine kinase (ATM) under chemotherapy, thus initiating downstream pathways related to DNA repair. In summary, the loss of NEIL3 promotes chemotherapy resistance in prostate cancer, and NEIL3 may serve as a diagnostic marker for chemotherapy-resistant patients.
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spelling pubmed-80714372021-04-26 Deficiency of NEIL3 Enhances the Chemotherapy Resistance of Prostate Cancer Wang, Yiwei Xu, Liuyue Shi, Shanshan Wu, Sha Meng, Ruijie Chen, Huifang Jiang, Zhenyou Int J Mol Sci Article Acquired treatment resistance is an important cause of death in prostate cancer, and this study aimed to explore the mechanisms of chemotherapy resistance in prostate cancer. We employed castration-resistant prostate cancer (CRPC), neuroendocrine prostate cancer (NEPC), and chemotherapy-resistant prostate cancer datasets to screen for potential target genes. The Cancer Genome Atlas (TCGA) was used to detect the correlation between the target genes and prognosis and clinical characteristics. Nei endonuclease VIII-like 3 (NEIL3) knockdown cell lines were constructed with RNA interference. Prostate cancer cells were treated with enzalutamide for the androgen deprivation therapy (ADT) model, and with docetaxel and cisplatin for the chemotherapy model. Apoptosis and the cell cycle were examined using flow cytometry. RNA sequencing and western blotting were performed in the knockdown Duke University 145 (DU145) cell line to explore the possible mechanisms. The TCGA dataset demonstrated that high NEIL3 was associated with a high T stage and Gleason score, and indicated a possibility of lymph node metastasis, but a good prognosis. The cell therapy models showed that the loss of NEIL3 could promote the chemotherapy resistance (but not ADT resistance) of prostate cancer (PCa). Flow cytometry revealed that the loss of NEIL3 in PCa could inhibit cell apoptosis and cell cycle arrest under cisplatin treatment. RNA sequencing showed that the knockdown of NEIL3 changes the expression of neuroendocrine-related genes. Further western blotting revealed that the loss of NEIL3 could significantly promote the phosphorylation of ATR serine/threonine kinase (ATR) and ATM serine/threonine kinase (ATM) under chemotherapy, thus initiating downstream pathways related to DNA repair. In summary, the loss of NEIL3 promotes chemotherapy resistance in prostate cancer, and NEIL3 may serve as a diagnostic marker for chemotherapy-resistant patients. MDPI 2021-04-15 /pmc/articles/PMC8071437/ /pubmed/33921035 http://dx.doi.org/10.3390/ijms22084098 Text en © 2021 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
Wang, Yiwei
Xu, Liuyue
Shi, Shanshan
Wu, Sha
Meng, Ruijie
Chen, Huifang
Jiang, Zhenyou
Deficiency of NEIL3 Enhances the Chemotherapy Resistance of Prostate Cancer
title Deficiency of NEIL3 Enhances the Chemotherapy Resistance of Prostate Cancer
title_full Deficiency of NEIL3 Enhances the Chemotherapy Resistance of Prostate Cancer
title_fullStr Deficiency of NEIL3 Enhances the Chemotherapy Resistance of Prostate Cancer
title_full_unstemmed Deficiency of NEIL3 Enhances the Chemotherapy Resistance of Prostate Cancer
title_short Deficiency of NEIL3 Enhances the Chemotherapy Resistance of Prostate Cancer
title_sort deficiency of neil3 enhances the chemotherapy resistance of prostate cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071437/
https://www.ncbi.nlm.nih.gov/pubmed/33921035
http://dx.doi.org/10.3390/ijms22084098
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