Induction of robust de novo centrosome amplification, high-grade spindle multipolarity and metaphase catastrophe: a novel chemotherapeutic approach.
Induction of robust de novo centrosome amplification, high-grade spindle multipolarity and metaphase catastrophe: a novel chemotherapeutic approach.
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DOI：
10.1038/cddis.2012.82
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发表时间：
2012-07-12
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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中心体扩增（CA）和由此产生的染色体不稳定性长期以来与肿瘤发生有关。然而，在有丝分裂过程中，CA的加剧和中心体的无情脱簇会产生强大的纺锤体多极性（SM），并可能诱导细胞死亡。最近，我们证实了一种noscapinoid成员，还原溴oscapine， (S)-3-(R)-9-溴-5-（4,5-二甲氧基-1,3-二氢异苯并呋喃-1-基）-4-甲氧基-6-甲基-5,6,7,8-四氢-[1,3]dioxolo-[4,5-g]异喹啉（Red-Br-nos），在前列腺癌PC-3细胞中诱导活性氧（ROS）介导的自噬和caspase非依赖性死亡。本研究表明，Red-Br-nos诱导ros依赖性DNA损伤，导致PC-3细胞发生高级别CA和SM。与阿霉素引起双链DNA断裂和伴随“模板化”CA的慢性G2阻滞不同，red - br -no介导的DNA损伤在短暂的S/G2停滞期间引发重新CA，随后是检查点取消和有丝分裂进入，形成异常的有丝分裂图形，具有额外的纺锤杆。在ROS抑制剂铁的存在下，多极表型的衰减表明，ROS介导的DNA损伤是驱动CA和SM的部分原因。虽然少数细胞（~ 5%）在“后期突变”后产生异常的细胞分裂，但大多数有丝分裂阻滞的细胞（~ 70%）屈服于“中期突变”，这是半胱天冬酶无关的。本报告首次报道了noscapinoid家族成员在亲本中心体存在的情况下快速新生中心体形成，通过一种独特的机制触发致死性SM，这一机制与其他ros诱导剂、传统dna损伤剂以及其他微管结合药物不同。
Centrosome amplification (CA) and resultant chromosomal instability have long been associated with tumorigenesis. However, exacerbation of CA and relentless centrosome declustering engender robust spindle multipolarity (SM) during mitosis and may induce cell death. Recently, we demonstrated that a noscapinoid member, reduced bromonoscapine, (S)-3-(R)-9-bromo-5-(4,5-dimethoxy-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo-[4,5-g]isoquinoline (Red-Br-nos), induces reactive oxygen species (ROS)-mediated autophagy and caspase-independent death in prostate cancer PC-3 cells. Herein, we show that Red-Br-nos induces ROS-dependent DNA damage that resulted in high-grade CA and SM in PC-3 cells. Unlike doxorubicin, which causes double-stranded DNA breaks and chronic G2 arrest accompanied by ‘templated' CA, Red-Br-nos-mediated DNA damage elicits de novo CA during a transient S/G2 stall, followed by checkpoint abrogation and mitotic entry to form aberrant mitotic figures with supernumerary spindle poles. Attenuation of multipolar phenotype in the presence of tiron, a ROS inhibitor, indicated that ROS-mediated DNA damage was partly responsible for driving CA and SM. Although a few cells (∼5%) yielded to aberrant cytokinesis following an ‘anaphase catastrophe', most mitotically arrested cells (∼70%) succumbed to ‘metaphase catastrophe,' which was caspase-independent. This report is the first documentation of rapid de novo centrosome formation in the presence of parent centrosome by a noscapinoid family member, which triggers death-inducing SM via a unique mechanism that distinguishes it from other ROS-inducers, conventional DNA-damaging agents, as well as other microtubule-binding drugs.
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影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
DOI：
10.1038/nrm2718
发表时间：
2009-07
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
11.2
作者：
Aneja, R;Lopus, M;Joshi, HC
通讯作者：
Joshi, HC
影响因子：
11.8
作者：
Kleylein-Sohn, Julia;Westendorf, Jens;Nigg, Erich A.
通讯作者：
Nigg, Erich A.
影响因子：
21.3
作者：
Habedanck, R;Stierhof, YD;Nigg, EA
通讯作者：
Nigg, EA