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Camptothecin Effectively Regulates Germline Differentiation through Bam–Cyclin A Axis in Drosophila melanogaster

Camptothecin (CPT), first isolated from Chinese tree Camptotheca acuminate, produces rapid and prolonged inhibition of DNA synthesis and induction of DNA damage by targeting topoisomerase I (top1), which is highly activated in cancer cells. CPT thus exhibits remarkable anticancer activities in vario...

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Autores principales: Zhang, Jing, Zhang, Shijie, Sun, Zhipeng, Cai, Yu, Zhong, Guohua, Yi, Xin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9864452/
https://www.ncbi.nlm.nih.gov/pubmed/36675143
http://dx.doi.org/10.3390/ijms24021617
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author Zhang, Jing
Zhang, Shijie
Sun, Zhipeng
Cai, Yu
Zhong, Guohua
Yi, Xin
author_facet Zhang, Jing
Zhang, Shijie
Sun, Zhipeng
Cai, Yu
Zhong, Guohua
Yi, Xin
author_sort Zhang, Jing
collection PubMed
description Camptothecin (CPT), first isolated from Chinese tree Camptotheca acuminate, produces rapid and prolonged inhibition of DNA synthesis and induction of DNA damage by targeting topoisomerase I (top1), which is highly activated in cancer cells. CPT thus exhibits remarkable anticancer activities in various cancer types, and is a promising therapeutic agent for the treatment of cancers. However, it remains to be uncovered underlying its cytotoxicity toward germ cells. In this study we found that CPT, a cell cycle-specific anticancer agent, reduced fecundity and exhibited significant cytotoxicity toward GSCs and two-cell cysts. We showed that CPT induced GSC loss and retarded two-cell cysts differentiation in a niche- or apoptosis-independent manner. Instead, CPT induced ectopic expression of a differentiation factor, bag of marbles (Bam), and regulated the expression of cyclin A, which contributed to GSC loss. In addition, CPT compromised two-cell cysts differentiation by decreasing the expression of Bam and inducing cell arrest at G1/S phase via cyclin A, eventually resulting in two-cell accumulation. Collectively, this study demonstrates, for the first time in vivo, that the Bam–cyclin A axis is involved in CPT-mediated germline stem cell loss and two-cell cysts differentiation defects via inducing cell cycle arrest, which could provide information underlying toxicological effects of CPT in the productive system, and feature its potential to develop as a pharmacology-based germline stem cell regulation agent.
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spelling pubmed-98644522023-01-22 Camptothecin Effectively Regulates Germline Differentiation through Bam–Cyclin A Axis in Drosophila melanogaster Zhang, Jing Zhang, Shijie Sun, Zhipeng Cai, Yu Zhong, Guohua Yi, Xin Int J Mol Sci Article Camptothecin (CPT), first isolated from Chinese tree Camptotheca acuminate, produces rapid and prolonged inhibition of DNA synthesis and induction of DNA damage by targeting topoisomerase I (top1), which is highly activated in cancer cells. CPT thus exhibits remarkable anticancer activities in various cancer types, and is a promising therapeutic agent for the treatment of cancers. However, it remains to be uncovered underlying its cytotoxicity toward germ cells. In this study we found that CPT, a cell cycle-specific anticancer agent, reduced fecundity and exhibited significant cytotoxicity toward GSCs and two-cell cysts. We showed that CPT induced GSC loss and retarded two-cell cysts differentiation in a niche- or apoptosis-independent manner. Instead, CPT induced ectopic expression of a differentiation factor, bag of marbles (Bam), and regulated the expression of cyclin A, which contributed to GSC loss. In addition, CPT compromised two-cell cysts differentiation by decreasing the expression of Bam and inducing cell arrest at G1/S phase via cyclin A, eventually resulting in two-cell accumulation. Collectively, this study demonstrates, for the first time in vivo, that the Bam–cyclin A axis is involved in CPT-mediated germline stem cell loss and two-cell cysts differentiation defects via inducing cell cycle arrest, which could provide information underlying toxicological effects of CPT in the productive system, and feature its potential to develop as a pharmacology-based germline stem cell regulation agent. MDPI 2023-01-13 /pmc/articles/PMC9864452/ /pubmed/36675143 http://dx.doi.org/10.3390/ijms24021617 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
Zhang, Jing
Zhang, Shijie
Sun, Zhipeng
Cai, Yu
Zhong, Guohua
Yi, Xin
Camptothecin Effectively Regulates Germline Differentiation through Bam–Cyclin A Axis in Drosophila melanogaster
title Camptothecin Effectively Regulates Germline Differentiation through Bam–Cyclin A Axis in Drosophila melanogaster
title_full Camptothecin Effectively Regulates Germline Differentiation through Bam–Cyclin A Axis in Drosophila melanogaster
title_fullStr Camptothecin Effectively Regulates Germline Differentiation through Bam–Cyclin A Axis in Drosophila melanogaster
title_full_unstemmed Camptothecin Effectively Regulates Germline Differentiation through Bam–Cyclin A Axis in Drosophila melanogaster
title_short Camptothecin Effectively Regulates Germline Differentiation through Bam–Cyclin A Axis in Drosophila melanogaster
title_sort camptothecin effectively regulates germline differentiation through bam–cyclin a axis in drosophila melanogaster
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9864452/
https://www.ncbi.nlm.nih.gov/pubmed/36675143
http://dx.doi.org/10.3390/ijms24021617
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