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驱动蛋白在癌细胞力学中的作用。

Role of a Kinesin Motor in Cancer Cell Mechanics.

机构信息

Institute for Medicine and Engineering , University of Pennsylvania , Philadelphia , Pennsylvania 19104 , United States.

Institute of Nuclear Physics , Polish Academy of Sciences , PL-31342 Krakow 31-342 , Poland.

出版信息

Nano Lett. 2019 Nov 13;19(11):7691-7702. doi: 10.1021/acs.nanolett.9b02592. Epub 2019 Oct 7.

Abstract

Molecular motors play important roles in force generation, migration, and intracellular trafficking. Changes in specific motor activities are altered in numerous diseases. KIF20A, a motor protein of the kinesin-6 family, is overexpressed in bladder cancer, and KIF20A levels correlate negatively with clinical outcomes. We report here a new role for the KIF20A kinesin motor protein in intracellular mechanics. Using optical tweezers to probe intracellular mechanics and surface AFM to probe cortical mechanics, we first confirm that bladder urothelial cells soften with an increasing cancer grade. We then show that inhibiting KIF20A makes the intracellular environment softer for both high- and low-grade bladder cancer cells. Upon inhibition of KIF20A, cortical stiffness also decreases in lower grade cells, while it surprisingly increases in higher grade malignant cells. Changes in cortical stiffness correlate with the interaction of KIF20A with myosin IIA. Moreover, KIF20A inhibition negatively regulates bladder cancer cell motility irrespective of the underlying substrate stiffness. Our results reveal a central role for a microtubule motor in cell mechanics and migration in the context of bladder cancer.

摘要

分子马达在力的产生、迁移和细胞内运输中发挥着重要作用。特定马达活性的变化在许多疾病中都发生了改变。驱动蛋白-20A(KIF20A)是驱动蛋白-6 家族的一种马达蛋白,在膀胱癌中过表达,并且 KIF20A 水平与临床结果呈负相关。我们在这里报告了 KIF20A 驱动蛋白马达在细胞内力学中的一个新作用。我们使用光镊探测细胞内力学,使用原子力显微镜(AFM)探测皮质力学,首先证实了随着癌症分级的增加,膀胱尿路上皮细胞会变软。然后我们表明,抑制 KIF20A 会使高低分级膀胱癌细胞的细胞内环境变软。在抑制 KIF20A 后,低分级细胞的皮质硬度也会降低,而令人惊讶的是,高分级恶性细胞的皮质硬度会增加。皮质硬度的变化与 KIF20A 与肌球蛋白 IIA 的相互作用有关。此外,无论基础底物硬度如何,KIF20A 抑制均可负调节膀胱癌细胞的迁移能力。我们的结果揭示了微管马达在膀胱癌中细胞力学和迁移中的核心作用。

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