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

Jing Zhang, Shijie Zhang, Zhipeng Sun, Yu Cai, Guohua Zhong, Xin Yi

International journal of molecular sciences 2023 Jan 13

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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.

Citation

Jing Zhang, Shijie Zhang, Zhipeng Sun, Yu Cai, Guohua Zhong, Xin Yi. Camptothecin Effectively Regulates Germline Differentiation through Bam-Cyclin A Axis in Drosophila melanogaster. International journal of molecular sciences. 2023 Jan 13;24(2)