Early RB94-produced cytotoxicity in cancer cells is independent of caspase activation or 50 kb DNA fragmentation.
Early RB94-produced cytotoxicity in cancer cells is independent of caspase activation or 50 kb DNA fragmentation.
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DOI：
10.1038/cgt.2008.54
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发表时间：
2009-01
影响因子：
6.4
通讯作者：
中科院分区：
文献类型：
--
作者：
RB 94缺乏全长RB（RB 110）的NH 2-末端112个氨基酸残基，是比RB 110更有效的癌细胞生长抑制剂，对所研究的所有癌细胞系具有细胞毒性，与其遗传异常无关。虽然我们最初认为RB 94诱导的细胞死亡是半胱天冬酶依赖性的，但这种半胱天冬酶激活现在似乎是晚期事件。在用Ad-RB 94转导后48小时仍保持附着的细胞显示出核增大、外周核染色质浓缩和经常微核化等变化。此外，细胞是TUNEL阳性的，但没有显示半胱天冬酶3或9的裂解。仅在细胞脱离后才观察到半胱天冬酶3和9的切割。这些TUNEL阳性细胞既没有细胞色素C线粒体易位通常发现在典型的凋亡细胞，也没有DNA梯状指示寡核小体DNA片段化。此外，尽管在这些TUNEL阳性细胞中产生50 kb DNA片段，其依赖于凋亡诱导因子（AIF），但通过siAIF抑制这种片段化并不抑制TUNEL形成或细胞毒性。由于RB 94将很快用于基因治疗，进一步了解这些杀死癌细胞的早期变化的分子基础是我们目前特别重要的目标之一。
RB94, which lacks the NH2-terminal 112 amino acid residues of the full-length RB (RB110) is a more potent inhibitor of cancer cell growth than RB 110, being cytotoxic to all cancer cell lines studied, independent of their genetic abnormalities. Although we initially thought RB94 induced cell death was caspase dependent, such caspase activation now appears to be a late event. Cells that remained attached 48 hr after transduction with Ad-RB94 showed, among other changes, nuclear enlargement, peripheral nuclear chromatin condensation, and often micronucleation. In addition, the cells were TUNEL positive but showed no cleavage of caspase 3 or 9. Only after the cells detached was cleavage of both caspase 3 and 9 observed. These TUNEL positive cells showed neither cytochrome C mitochondrial translocation usually found in typical apoptotic cells nor DNA laddering indicative of oligonucleosomal DNA fragmentation. In addition, although 50 kb DNA fragmentation was produced in these TUNEL positive cells, which was dependent on apoptosis-inducing factor (AIF), inhibiting this fragmentation by siAIF did not inhibit TUNEL formation or cytotoxicity. Since RB94 will soon be used for gene therapy further understanding the molecular basis of these early changes in killing cancer cells is one of our particularly important present goals.
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影响因子：
8
作者：
Chapman, E. J.;Hurst, C. D.;Knowles, M. A.
通讯作者：
Knowles, M. A.
影响因子：
64.8
作者：
Susin, SA;Lorenzo, HK;Kroemer, G
通讯作者：
Kroemer, G
影响因子：
4.8
作者：
McConkey, DJ
通讯作者：
McConkey, DJ
DOI：
10.1084/jem.192.4.571
发表时间：
2000-08-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Susin SA;Daugas E;Ravagnan L;Samejima K;Zamzami N;Loeffler M;Costantini P;Ferri KF;Irinopoulou T;Prévost MC;Brothers G;Mak TW;Penninger J;Earnshaw WC;Kroemer G
通讯作者：
Kroemer G
影响因子：
11.5
作者：
Pirollo, Kathleen F.;Rait, Antonina;Chang, Esther H.
通讯作者：
Chang, Esther H.