Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Hiroshima, Japan.
Faculty of Health and Welfare Science, Okayama Prefectural University, Okayama, Japan.
J Cell Biochem. 2021 Jul;122(7):739-751. doi: 10.1002/jcb.29908. Epub 2021 Feb 14.
The appropriate regulation of spindle orientation maintains proper tissue homeostasis and avoids aberrant tissue repair or regeneration. Spindle misorientation due to imbalance or improper functioning leads to a loss of tissue integrity and aberrant growth, such as tissue loss or overgrowth. Pharmacological manipulation to prevent spindle misorientation will enable a better understanding of how spindle orientation is involved in physiological and pathological conditions and will provide therapeutic possibilities to treat patients associated with abnormal tissue function caused by spindle misorientation. N-terminal-deleted Rho guanine nucleotide dissociation inhibitor β (RhoGDIβ/RhoGDI2/LyGDI) produced by caspase-3 activation perturbs spindle orientation in surviving cells following exposure to either ionizing radiation or UVC. Thus, presumably, RhoGDIβ cleaved by caspase-3 activation acts as a determinant of radiation-induced spindle misorientation that promote aberrant tissue repair due to deregulation of directional organization of cell population and therefore becomes a potential target of drugs to prevent such response. The objective of this study was to screen and identify chemicals that suppress RhoGDIβ expression. We focused our attention on ascorbic acid (AA) derivatives because of their impact on the maintenance of skin tissue homeostasis. Here, we screened for AA derivatives that suppress RhoGDIβ expression in HeLa cells and identified a lipophilic derivative, 2-O-octadecylascorbic acid (2-OctadecylAA), as a novel RhoGDIβ inhibitor that ameliorated ionizing radiation-induced abnormal spindle orientations. Among all examined AA derivatives, which were also antioxidative, the inhibition activity was specific to 2-OctadecylAA. Therefore, this activity was not due to simple antioxidant properties. 2-OctadecylAA was previously shown to prevent hepatocellular carcinoma development. Our findings suggest that the anticarcinogenic effects of 2-OctadecylAA are partly due to RhoGDIβ inhibition mechanisms by which spindle orientation perturbations are attenuated. Thus, the molecular targeting features of RhoGDIβ warrant its further development for the treatment or control of spindle orientation abnormalities that affect epithelial homeostasis.
纺锤体方向的适当调节维持了组织的正常稳态，并避免了组织修复或再生的异常。由于失衡或功能不当导致的纺锤体错位会导致组织完整性的丧失和异常生长，例如组织缺失或过度生长。通过药物操作来防止纺锤体错位，将有助于更好地理解纺锤体方向如何参与生理和病理条件，并为治疗因纺锤体错位导致的异常组织功能的患者提供治疗可能性。半胱天冬酶-3 激活产生的 N 端缺失的 Rho 鸟嘌呤核苷酸解离抑制剂β（RhoGDIβ/RhoGDI2/LyGDI）扰乱了暴露于电离辐射或 UVC 后的存活细胞中的纺锤体方向。因此，推测半胱天冬酶-3 激活切割的 RhoGDIβ 作为导致纺锤体错位的决定因素，通过细胞群体定向组织的失调促进异常组织修复，因此成为预防这种反应的药物的潜在靶点。本研究的目的是筛选和鉴定抑制 RhoGDIβ 表达的化学物质。我们将注意力集中在抗坏血酸（AA）衍生物上，因为它们对维持皮肤组织稳态有影响。在这里，我们筛选了抑制 HeLa 细胞中 RhoGDIβ 表达的 AA 衍生物，并鉴定出一种亲脂性衍生物 2-O-辛基抗坏血酸（2-OctadecylAA），它是一种新型的 RhoGDIβ 抑制剂，可改善电离辐射诱导的异常纺锤体方向。在所有检查的 AA 衍生物中，它们也是抗氧化剂，抑制活性是 2-OctadecylAA 特有的。因此，这种活性不是由于简单的抗氧化特性。2-OctadecylAA 先前被证明可以预防肝癌的发展。我们的研究结果表明，2-OctadecylAA 的抗癌作用部分归因于 RhoGDIβ 抑制机制，通过该机制，纺锤体方向的扰动得到减弱。因此，RhoGDIβ 的分子靶向特征需要进一步开发，以治疗或控制影响上皮稳态的纺锤体方向异常。
