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

• Published in: International journal of molecular sciences 2023-01, Vol.24 (2), p.1617
• Main Authors: Zhang, Jing, Zhang, Shijie, Sun, Zhipeng, Cai, Yu, Zhong, Guohua, Yi, Xin
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Bam; Biocompatibility; Camptothecin; Camptothecin - metabolism; Camptothecin - pharmacology; Cancer; Cell cycle; Cell Cycle Checkpoints; Cell Differentiation; Chemical compounds; Cyclin A; Cyclin A - metabolism; Cyclins - metabolism; Cysts; Cysts - metabolism; Cytotoxicity; Differentiation; DNA biosynthesis; DNA damage; DNA topoisomerase; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - metabolism; Ectopic expression; Fecundity; Females; Germ cells; Germ Cells - metabolism; In vivo methods and tests; Insects; Ovaries; Pharmacology; Phase transitions; S phase; Stem cells
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24021617

Camptothecin (CPT), first isolated from Chinese tree , 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.