Ectopically expressed perforin-1 is proapoptotic in tumor cell lines by increasing caspase-3 activity and the nuclear translocation of cytochrome C.
Ectopically expressed perforin-1 is proapoptotic in tumor cell lines by increasing caspase-3 activity and the nuclear translocation of cytochrome C.
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异位表达的 Perforin-1 通过增加 Caspase-3 活性和细胞色素 c 的核转位促进肿瘤细胞系凋亡
DOI：
10.1371/journal.pone.0040639
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Yang AG
中科院分区：
文献类型：
--
作者：
Wang LF;Wang F;Li JT;Wen WH;Zhao J;Jia LT;Meng YL;Cao YX;Yao LB;Chen SY;Xu YM;Yang AG
穿孔素-1 （Perforin-1， PRF）是一种细胞毒性淋巴细胞成孔蛋白，在细胞毒性T细胞和自然杀伤细胞的作用中起重要作用，导致异常体细胞的溶解，病毒感染细胞和肿瘤的消除。脱粒后，PRF将自身插入靶细胞的质膜，形成一个孔。随后，促凋亡颗粒酶（包括颗粒酶B、A、M等）易位进入细胞质，为蛋白酶提供了许多促进裂解后细胞凋亡的蛋白质底物。这些蛋白酶被认为是靶细胞凋亡的主要刽子手。尽管PRF和颗粒酶成分在这一过程中都是至关重要的，并且在某种程度上参与诱导靶细胞死亡，但在颗粒酶缺乏的小鼠中，抑制肿瘤生长仍然是有效的。目前尚不清楚PRF是否能单独抑制肿瘤。在这项研究中，我们发现在没有颗粒酶的情况下，PRF单独的强迫异位表达可以介导癌细胞的细胞死亡。值得注意的是，在人Hep G2、SK-BR-3和HeLa细胞中，全长和截断的活性形式PRF的短暂表达均可诱导明显的细胞生长抑制和细胞死亡，表现为染色体凝聚和DNA断裂，caspase-3活性增加，线粒体释放凋亡诱导因子（AIF）和细胞色素c。这种prf诱导的细胞死亡可以通过泛半胱天冬酶抑制剂（Z-VAD）和线粒体保护剂（TAT-BH4）来消除。这些结果表明，异位表达的PRF具有诱导细胞凋亡的能力，并且在异位表达的细胞中，PRF本身足以诱导凋亡细胞死亡。考虑到这一点，我们的研究结果提示使用PRF作为促凋亡基因用于肿瘤治疗的可能性。
Perforin-1 (PRF), a cytotoxic lymphocyte pore-forming protein, plays an important role in the action of cytotoxic T cells and natural killer cells in that it causes the lysis of abnormal body cells and the elimination of virus-infected cells and tumors. Upon degranulation, PRF inserts itself into the target cell’s plasma membrane, forming a pore. The subsequent translocation of pro-apoptotic granzymes (including granzyme B, A, M et al.) into the cytoplasm provides the proteases with access to numerous protein substrates that promote apoptosis after cleavage. These proteases are believed to be the main executioners of target cell apoptosis. Although the PRF and granzyme components are both critical to this process and in some way involved in inducing cell death in target cells, the inhibition of tumor growth could still be efficient in granzyme-deficient mice. It is unclear whether PRF alone can suppress tumors. In this study, we discovered that forced ectopic expression of PRF alone, in the absence of granzymes, could mediate cell death in cancer cells. Notably, transient expression of both full-length and truncated active-form PRF in human Hep G2, SK-BR-3, and HeLa cells was found to induce apparent cell growth inhibition and cell death, as evidenced by chromosome condensation and DNA fragmentation, increased caspase-3 activity, and the release of apoptosis inducing factor (AIF) and cytochrome c from the mitochondria. This PRF-induced cell death could be abrogated by pan-caspase inhibitor (Z-VAD) and mitochondria protector (TAT-BH4). The implication of these results is that ectopically expressed PRF has apoptosis-inducing abilities, and PRF alone is sufficient to induce apoptotic cell death in cells with ectopic expression. Taking this into consideration, our results suggest the possibility of using PRF as a pro-apoptotic gene for tumor therapeutics.
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影响因子：
64.8
作者：
KAGI, D;LEDERMANN, B;HENGARTNER, H
通讯作者：
HENGARTNER, H
影响因子：
4.4
作者：
Packard, Beverly Z.;Telford, William G.;Henkart, Pierre A.
通讯作者：
Henkart, Pierre A.
Granzyme K 降解氧化还原/DNA 修复酶 Ape1，引发靶细胞的氧化应激，从而导致细胞毒性。
影响因子：
3.6
作者：
Guo, Yuming;Chen, Jun;Fan, Zusen
通讯作者：
Fan, Zusen
穿孔蛋白迅速诱导质膜磷脂触发器。
影响因子：
3.7
作者：
Metkar SS;Wang B;Catalan E;Anderluh G;Gilbert RJ;Pardo J;Froelich CJ
通讯作者：
Froelich CJ
影响因子：
32.4
作者：
Brennan, Amelia J.;Chia, Jenny;Voskoboinik, Ilia
通讯作者：
Voskoboinik, Ilia