Anjum R, Joshi P, Khar A
Centre for Cellular & Molecular Biology, Uppal Road, Hyderabad 500 007, India.
Cell Death Differ. 2001 Oct;8(10):1038-46. doi: 10.1038/sj.cdd.4400915.
The ability to selectively induce apoptosis in tumor cells is the prime goal in cancer immunotherapy and aims at identifying potential molecular targets, regulating this process. Here we show that the sera from the animals which had spontaneously rejected the AK-5 tumor (a rat histiocytoma) had an effective and potent ability to counteract and kill tumor cells by inducing apoptosis, with a high degree of specificity. Apoptosis induced by the serum factor involved the activation of caspases and cytochrome c release to the cytosol. A reduction in mitochondrial transmembrane potential (Delta psi(m)) occurred considerably later than cytochrome c translocation. The anti-apoptotic protein Bcl-2 and the pancaspase inhibitor zVAD-fmk did not prevent cytochrome c release, but completely blocked the reduction in Delta psi(m), DNA fragmentation and apoptosis. Cyclosporin A (CsA), an inhibitor of the mitochondrial permeability transition (MPT) pore had no effect on cytochrome c release and apoptosis mediated by serum factor in AK-5 cells, suggesting that apoptosis was independent of MPT. Taken together these results suggest that the serum factor in conjunction with the immune cells may be participating in the efficient rejection of the tumor in syngeneic hosts and Delta psi(m) disruption but not cytochrome c release, is a critical and decisive event to trigger apoptotic cell death induced by the serum factor in AK-5 tumor cells.
在肿瘤细胞中选择性诱导凋亡的能力是癌症免疫治疗的主要目标，旨在识别潜在的分子靶点并调节这一过程。在此我们表明，来自自发排斥AK-5肿瘤（一种大鼠组织细胞瘤）动物的血清具有通过诱导凋亡来对抗和杀死肿瘤细胞的有效且强大的能力，且具有高度特异性。血清因子诱导的凋亡涉及半胱天冬酶的激活以及细胞色素c释放到细胞质中。线粒体跨膜电位（Δψm）的降低比细胞色素c易位发生得晚得多。抗凋亡蛋白Bcl-2和泛半胱天冬酶抑制剂zVAD-fmk不能阻止细胞色素c的释放，但能完全阻断Δψm的降低、DNA片段化和凋亡。线粒体通透性转换（MPT）孔抑制剂环孢素A（CsA）对AK-5细胞中血清因子介导的细胞色素c释放和凋亡没有影响，这表明凋亡与MPT无关。综上所述，这些结果表明血清因子与免疫细胞可能共同参与了同基因宿主中肿瘤的有效排斥，并且Δψm的破坏而非细胞色素c的释放是触发AK-5肿瘤细胞中血清因子诱导的凋亡性细胞死亡的关键决定性事件。
