Zhang Lin Jie, Hao Yuan Zhang, Hu Chun Song, Ye Yan, Xie Qi Peng, Thorne Rick F, Hersey Peter, Zhang Xu Dong
Department of Immunology, The Anhui Medical University, Hefei, China.
Anticancer Drugs. 2008 Feb;19(2):159-66. doi: 10.1097/CAD.0b013e3282f30d05.
Although cisplatin has been shown to induce both apoptosis and necrosis in cancer cells, the potential interconnections between these modes of cell death induced by the drug remain unknown. We studied this phenomenon in gastric cancer cell lines and identified one cell line (SGC-7901) that underwent apoptosis, and another cell line (BGC-823) that primarily underwent nonapoptotic cell death, in response to cisplatin. Apoptosis in cisplatin-treated SGC-7901 cells seemed to be caspase dependent and was mediated, at least in part, by the BH3-only protein, Noxa. This was evidenced by the rapid upregulation of Noxa and inhibition of apoptosis by small interfering RNA knockdown of Noxa. Nonapoptotic cell death induced by cisplatin in BGC-823 cells was characterized by lack of DNA fragmentation, delayed externalization of phosphatidylserine, caspase independence, plasma membrane disruption, and intracellular vacuole formation, indicative of necrosis. Surprisingly, blockage of apoptosis induction by a general caspase inhibitor or by Noxa small interfering RNA in SGC-7901 failed to protect against cisplatin-induced cell death. Under such conditions, SGC-7901 cells displayed cellular features associated with necrosis. Cisplatin-induced apoptosis, thus, seems to precede necrosis when the apoptotic machinery is operative. When the apoptosis program is defective, necrotic cell death takes place as an alternative pathway leading to cell demise. Induction of different modes of cell death that are interrelated in the same cells by cisplatin has the potential to be exploited in formulating new adjuvant cancer therapies.
尽管顺铂已被证明可诱导癌细胞发生凋亡和坏死，但该药物诱导的这些细胞死亡模式之间的潜在联系仍不清楚。我们在胃癌细胞系中研究了这一现象，发现一种细胞系（SGC - 7901）对顺铂的反应是发生凋亡，另一种细胞系（BGC - 823）对顺铂的反应主要是发生非凋亡性细胞死亡。顺铂处理的SGC - 7901细胞中的凋亡似乎依赖于半胱天冬酶，并且至少部分是由仅含BH3结构域的蛋白Noxa介导的。Noxa的快速上调以及通过小干扰RNA敲低Noxa抑制凋亡证明了这一点。顺铂在BGC - 823细胞中诱导的非凋亡性细胞死亡的特征是缺乏DNA片段化、磷脂酰丝氨酸的外化延迟、不依赖半胱天冬酶、质膜破坏和细胞内空泡形成，表明是坏死。令人惊讶的是，在SGC - 7901细胞中，用一般的半胱天冬酶抑制剂或Noxa小干扰RNA阻断凋亡诱导并不能防止顺铂诱导的细胞死亡。在这种情况下，SGC - 7901细胞表现出与坏死相关的细胞特征。因此，当凋亡机制起作用时，顺铂诱导的凋亡似乎先于坏死。当凋亡程序有缺陷时，坏死性细胞死亡作为导致细胞死亡的替代途径发生。顺铂在同一细胞中诱导不同但相互关联的细胞死亡模式，这有可能被用于制定新的辅助癌症治疗方法。
