Laboratory of Signaling and Pharmacological Activity, Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea.
Sci Rep. 2021 Dec 6;11(1):23490. doi: 10.1038/s41598-021-02503-9.
Paclitaxel is an anti-microtubule agent that has been shown to induce cell death in gastric cancer. However, the detailed mechanism of action is unclear. In this study, we reveal that the paclitaxel-induced cell death mechanism involves mitotic catastrophe, autophagy and apoptosis in AGS cells. Paclitaxel induced intrinsic apoptosis by activating caspase-3, caspase-9 and PARP. In addition, the significant increase in autophagy marker LC3B-II, together with Atg5, class III PI3K and Beclin-1, and the down-regulation of p62 following paclitaxel treatment verified that paclitaxel induced autophagy. Further experiments showed that paclitaxel caused mitotic catastrophe, cell cycle arrest of the accumulated multinucleated giant cells at the G2/M phase and induction of cell death in 24 h. Within 48 h, the arrested multinucleated cells escaped mitosis by decreasing cell division regulatory proteins and triggered cell death. Cells treated with paclitaxel for 48 h were grown in fresh medium for 24 h and checked for CDC2, CDC25C and lamin B1 protein expressions. These proteins had decreased significantly, indicating that the remaining cells became senescent. In conclusion, it is suggested that paclitaxel-induced mitotic catastrophe is an integral part of the cell death mechanism, in addition to apoptosis and autophagy, in AGS cells.
紫杉醇是一种微管抑制剂，已被证明可诱导胃癌细胞死亡。然而，其详细的作用机制尚不清楚。在本研究中，我们揭示了紫杉醇诱导的AGS 细胞死亡机制涉及有丝分裂灾难、自噬和细胞凋亡。紫杉醇通过激活 caspase-3、caspase-9 和 PARP 诱导内在凋亡。此外，紫杉醇处理后自噬标志物 LC3B-II 的显著增加，以及 Atg5、III 类 PI3K 和 Beclin-1 的增加和 p62 的下调证实了紫杉醇诱导了自噬。进一步的实验表明，紫杉醇引起有丝分裂灾难，积累的多核巨细胞在 G2/M 期的细胞周期停滞，并在 24 小时内诱导细胞死亡。在 48 小时内，被阻滞的多核细胞通过减少细胞分裂调节蛋白而逃脱有丝分裂，并引发细胞死亡。用紫杉醇处理 48 小时的细胞在新鲜培养基中生长 24 小时，并检查 CDC2、CDC25C 和 lamin B1 蛋白的表达。这些蛋白显著减少，表明剩余的细胞进入衰老状态。总之，提示紫杉醇诱导的有丝分裂灾难是 AGS 细胞中细胞死亡机制的一个组成部分，除了细胞凋亡和自噬之外。
