Disrupted mitochondrial homeostasis coupled with mitotic arrest generates antineoplastic oxidative stress.
Disrupted mitochondrial homeostasis coupled with mitotic arrest generates antineoplastic oxidative stress.
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线粒体稳态破坏加上有丝分裂停滞会产生抗肿瘤氧化应激
DOI：
10.1038/s41388-021-02105-9
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发表时间：
2022-01
期刊：
影响因子：
8
通讯作者：
Shao C
中科院分区：
文献类型：
--
作者：
Hao X;Bu W;Lv G;Xu L;Hou D;Wang J;Liu X;Yang T;Zhang X;Liu Q;Gong Y;Shao C
活性氧(ROS)是各种细胞过程中的关键信号。过量的ROS会导致细胞死亡或衰老，并介导许多抗癌药物的治疗效果。最近的研究表明，在G2/M期阻滞过程中，ROS的积累越来越多，但其潜在的机制尚未完全阐明。在这里，我们表明，在抗癌剂TH287或紫杉醇处理的癌细胞中，导致M期停滞的线粒体大量积累，并产生过量的线粒体超氧化物，从而导致DNA氧化损伤，破坏细胞的生存和增殖。当细胞停滞在M期时，线粒体质量显著增加，线粒体功能受损，表现为线粒体膜电位降低，线粒体蛋白糖基化和乙酰化增加，以及代谢对糖酵解的依赖增加。Chk1功能中断会减慢细胞周期，避免M期停滞，并减轻线粒体的氧化应激。诱导有丝分裂和阻断线粒体的生物发生，减少线粒体积累，也减慢细胞周期和消除M停滞偶联的线粒体氧化应激。这些结果表明，细胞周期进程和线粒体稳态是相互依赖和协调的，线粒体稳态的破坏及其相关的氧化还原信号可能介导了M停滞诱导化疗药物的抗肿瘤作用。我们的发现提供了对滞留在M期的细胞命运的洞察，并对癌症治疗具有启示意义。
Reactive oxygen species (ROS) serve as critical signals in various cellular processes. Excessive ROS cause cell death or senescence and mediates the therapeutic effect of many cancer drugs. Recent studies showed that ROS increasingly accumulate during G2/M arrest, the underlying mechanism, however, has not been fully elucidated. Here, we show that in cancer cells treated with anticancer agent TH287 or paclitaxel that causes M arrest, mitochondria accumulate robustly and produce excessive mitochondrial superoxide, which causes oxidative DNA damage and undermines cell survival and proliferation. While mitochondrial mass is greatly increased in cells arrested at M phase, the mitochondrial function is compromised, as reflected by reduced mitochondrial membrane potential, increased SUMOylation and acetylation of mitochondrial proteins, as well as an increased metabolic reliance on glycolysis. CHK1 functional disruption decelerates cell cycle, spares the M arrest and attenuates mitochondrial oxidative stress. Induction of mitophagy and blockade of mitochondrial biogenesis, measures that reduce mitochondrial accumulation, also decelerate cell cycle and abrogate M arrest-coupled mitochondrial oxidative stress. These results suggest that cell cycle progression and mitochondrial homeostasis are interdependent and coordinated, and that impairment of mitochondrial homeostasis and the associated redox signaling may mediate the antineoplastic effect of the M arrest-inducing chemotherapeutics. Our findings provide insights into the fate of cells arrested at M phase and have implications in cancer therapy.
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影响因子：
3.7
作者：
Fu X;Wan S;Lyu YL;Liu LF;Qi H
通讯作者：
Qi H
影响因子：
24.5
作者：
Manic G;Signore M;Sistigu A;Russo G;Corradi F;Siteni S;Musella M;Vitale S;De Angelis ML;Pallocca M;Amoreo CA;Sperati F;Di Franco S;Barresi S;Policicchio E;De Luca G;De Nicola F;Mottolese M;Zeuner A;Fanciulli M;Stassi G;Maugeri-Saccà M;Baiocchi M;Tartaglia M;Vitale I;De Maria R
通讯作者：
De Maria R
DOI：
10.15252/embj.201592862
发表时间：
2016-04-01
期刊：
The EMBO journal
影响因子：
--
作者：
Correia-Melo C;Marques FD;Anderson R;Hewitt G;Hewitt R;Cole J;Carroll BM;Miwa S;Birch J;Merz A;Rushton MD;Charles M;Jurk D;Tait SW;Czapiewski R;Greaves L;Nelson G;Bohlooly-Y M;Rodriguez-Cuenca S;Vidal-Puig A;Mann D;Saretzki G;Quarato G;Green DR;Adams PD;von Zglinicki T;Korolchuk VI;Passos JF
通讯作者：
Passos JF
DOI：
10.1084/jem.20081297
发表时间：
2008-09-29
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chen C;Liu Y;Liu R;Ikenoue T;Guan KL;Liu Y;Zheng P
通讯作者：
Zheng P
影响因子：
5.3
作者：
Havens, Courtney G.;Ho, Alan;Dowdy, Steven F.
通讯作者：
Dowdy, Steven F.