持续性细胞皱缩在人上皮细胞凋亡过程中的必要性(英文)

Prerequisite role of persistent cell shrinkage in apoptosis of human epithelial cells

持续性细胞皱缩是凋亡发生的一个主要标志。近期研究发现细胞皱缩在细胞凋亡过程中并不是一个被动的次要事件。在各种细胞中,包括人上皮细胞,凋亡因子(apoptogen)刺激后马上发生全细胞皱缩,又称为凋亡性容积减小(apoptotic volume decrease,AVD),继而发生caspase激活、DNA片段化、细胞破裂死亡。K^+和Cl^-通道的激活导致KCl外流,诱导AVD发生。抑制AVD发生可以抑制细胞凋亡。AVD与调节性容积增加(regulatory volume increase,RVI)异常相伴发生时,人上皮性HeLa细胞发生持续性细胞皱缩。RVI功能受损时,高渗本身就能诱导HeLa细胞持续性细胞皱缩,继而凋亡。即使在正常渗透压、无凋亡因子刺激的情况下,将HeLa细胞置于缺乏Na^+或Cl^-的溶液也会导致细胞持续性皱缩,继而凋亡。因此,AVD诱导和RVI异常所导致的持续性细胞皱缩是人上皮细胞发生凋亡的首要条件。

Persistent cell volume reduction is a major hallmark of apoptosis. Recent studies have demonstrated that cell volume reduction is not a passive, secondary event of the apoptotic cell death process. Whole-cell shrinkage, termed apoptotic volume decrease （AVD）, takes place soon after stimulation with apoptogen and precedes caspase activation, DNA and cell fragmentation in a variety of cell types including human epithelial cells. The AVD induction is the result of KC1 efflux attained by activation of K^＋ and Cl^- channels. Inhibition of AVD induction leads to rescue of the cells from apoptosis. Since the AVD process is coupled to dysfunction of the regulatory volume increase （RVI）, apoptotic cells undergo persistent cell shrinkage in human epithelial HeLa cells. When the RVI mechanism was impaired, hypertonic stress itself induced not only persistent cell shrinkage but also apoptotic cell death in HeLa cells. Even under normotonic apoptogen-free conditions, exposure of HeLa cells to Na^- or Cl^--deficient solution alone can bring about persistent cell shrinkage and thereafter apoptotic cell death. Thus, it is concluded that persistent cell shrinkage, which comprises AVD induction and RVI dysfunction, is a prerequisite to apoptosis induction in human epithelial cells.