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Enhanced tumor cell killing by ultrasound after microtubule depolymerization
Bioengineering & Translational Medicine ( IF 6.1 ) Pub Date : 2021-05-26 , DOI: 10.1002/btm2.10233
Aditi Singh 1, 2 , Ajay Tijore 1 , Felix Margadant 1 , Chloe Simpson 1 , Deepak Chitkara 2 , Boon Chuan Low 1 , Michael Sheetz 1, 3
Affiliation  

Recent studies show that tumor cells are vulnerable to mechanical stresses and undergo calcium-dependent apoptosis (mechanoptosis) with mechanical perturbation by low-frequency ultrasound alone. To determine if tumor cells are particularly sensitive to mechanical stress in certain phases of the cell cycle, inhibitors of the cell-cycle phases are tested for effects on mechanoptosis. Most inhibitors show no significant effect, but inhibitors of mitosis that cause microtubule depolymerization increase the mechanoptosis. Surprisingly, ultrasound treatment also disrupts microtubules independent of inhibitors in tumor cells but not in normal cells. Ultrasound causes calcium entry through mechanosensitive Piezo1 channels that disrupts microtubules via calpain protease activation. Myosin IIA contractility is required for ultrasound-mediated mechanoptosis and microtubule disruption enhances myosin IIA contractility through activation of GEF-H1 and RhoA pathway. Further, ultrasound promotes contractility-dependent Piezo1 expression and localization to the peripheral adhesions where activated Piezo1 allows calcium entry to continue feedback loop. Thus, the synergistic action of ultrasound and nanomolar concentrations of microtubule depolymerizing agents can enhance tumor therapies.

中文翻译:

微管解聚后超声增强肿瘤细胞杀伤力

最近的研究表明,肿瘤细胞容易受到机械应力的影响,并在单独低频超声的机械扰动下发生钙依赖性细胞凋亡(机械凋亡)。为了确定肿瘤细胞在细胞周期的某些阶段是否对机械应力特别敏感,测试了细胞周期阶段的抑制剂对机械凋亡的影响。大多数抑制剂没有表现出明显的效果,但导致微管解聚的有丝分裂抑制剂会增加机械凋亡。令人惊讶的是,超声治疗还会破坏肿瘤细胞中的微管,而不受抑制剂的影响,但正常细胞中的微管却不会。超声波导致钙通过机械敏感的 Piezo1 通道进入,通过钙蛋白酶激活破坏微管。肌球蛋白 IIA 收缩性是超声介导的机械凋亡所必需的,微管破坏通过激活 GEF-H1 和 RhoA 途径增强肌球蛋白 IIA 收缩性。此外,超声促进收缩依赖性 Piezo1 表达并定位到外周粘连,其中激活的 Piezo1 允许钙进入以继续反馈循环。因此,超声和纳摩尔浓度的微管解聚剂的协同作用可以增强肿瘤治疗。
更新日期:2021-05-26
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