Tumor treating fields perturb the localization of septins and cause aberrant mitotic exit.
Tumor treating fields perturb the localization of septins and cause aberrant mitotic exit.
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DOI：
10.1371/journal.pone.0125269
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Swanson KD
中科院分区：
文献类型：
--
作者：
Gera N;Yang A;Holtzman TS;Lee SX;Wong ET;Swanson KD
化疗和放疗的抗肿瘤作用被认为是通过触发G1/S或G2/M细胞周期检查点介导的，而纺锤体毒物，如紫杉醇，通过启动纺锤体组装检查点来阻断中期退出。相比之下，我们发现150千赫（kHz）的交变电场，也称为肿瘤治疗场（TTFields），在从中期到后期的过渡期扰乱细胞。在有丝分裂期间暴露于TTFields的细胞显示正常进展，但表现出不受控制的膜起泡，与中期退出一致。这种交变电场影响细胞生理学的能力可能取决于它们与具有高偶极矩的蛋白质的相互作用。由Septin 2、6和7组成的有丝分裂Septin复合物具有2711 Debyes（D）的高计算偶极矩，并且在定位细胞动力学切割沟和控制其在进入期间的收缩中起核心作用。我们发现，在后期，TTFields抑制Septin定位到后期纺锤体中线和细胞动力学沟，以及其与微管在纤维连接蛋白上的细胞附着和铺展。在由于TTFields暴露导致异常中期退出后，细胞表现出异常核结构和细胞应激体征，包括细胞增殖总体降低，随后是受p53突变状态强烈影响的细胞凋亡。因此，TTFields能够通过特异性干扰参与细胞分裂的关键蛋白来减少细胞增殖，导致有丝分裂灾难和随后的细胞死亡。
The anti-tumor effects of chemotherapy and radiation are thought to be mediated by triggering G1/S or G2/M cell cycle checkpoints, while spindle poisons, such as paclitaxel, block metaphase exit by initiating the spindle assembly checkpoint. In contrast, we have found that 150 kilohertz (kHz) alternating electric fields, also known as Tumor Treating Fields (TTFields), perturbed cells at the transition from metaphase to anaphase. Cells exposed to the TTFields during mitosis showed normal progression to this point, but exhibited uncontrolled membrane blebbing that coincided with metaphase exit. The ability of such alternating electric fields to affect cellular physiology is likely to be dependent on their interactions with proteins possessing high dipole moments. The mitotic Septin complex consisting of Septin 2, 6 and 7, possesses a high calculated dipole moment of 2711 Debyes (D) and plays a central role in positioning the cytokinetic cleavage furrow, and governing its contraction during ingression. We showed that during anaphase, TTFields inhibited Septin localization to the anaphase spindle midline and cytokinetic furrow, as well as its association with microtubules during cell attachment and spreading on fibronectin. After aberrant metaphase exit as a consequence of TTFields exposure, cells exhibited aberrant nuclear architecture and signs of cellular stress including an overall decrease in cellular proliferation, followed by apoptosis that was strongly influenced by the p53 mutational status. Thus, TTFields are able to diminish cell proliferation by specifically perturbing key proteins involved in cell division, leading to mitotic catastrophe and subsequent cell death.
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影响因子：
4
作者：
Kirson, Eilon D.;Giladi, Moshe;Gurvich, Zoya;Itzhaki, Aviran;Mordechovich, Daniel;Schneiderman, Rosa S.;Wasserman, Yoram;Ryffel, Bernhard;Goldsher, Dorit;Palti, Yoram
通讯作者：
Palti, Yoram
DOI：
10.1083/jcb.201012143
发表时间：
2011-06-13
期刊：
The Journal of cell biology
影响因子：
--
作者：
DeMay BS;Bai X;Howard L;Occhipinti P;Meseroll RA;Spiliotis ET;Oldenbourg R;Gladfelter AS
通讯作者：
Gladfelter AS
影响因子：
14.9
作者：
Felder CE;Prilusky J;Silman I;Sussman JL
通讯作者：
Sussman JL
影响因子：
4.6
作者：
Field, CM;Coughlin, M;Sullivan, W
通讯作者：
Sullivan, W
影响因子：
56.9
作者：
Bunz, F;Dutriaux, A;Vogelstein, B
通讯作者：
Vogelstein, B