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首页> 外文期刊>Cellular Physiology and Biochemistry >A New Perspective for Osteosarcoma Therapy: Proteasome Inhibition by MLN9708/2238 Successfully Induces Apoptosis and Cell Cycle Arrest and Attenuates the Invasion Ability of Osteosarcoma Cells in Vitro
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A New Perspective for Osteosarcoma Therapy: Proteasome Inhibition by MLN9708/2238 Successfully Induces Apoptosis and Cell Cycle Arrest and Attenuates the Invasion Ability of Osteosarcoma Cells in Vitro

机译：骨肉瘤治疗的新观点：MLN9708 / 2238蛋白酶体抑制成功诱导细胞凋亡和细胞周期阻滞，并减轻骨肉瘤细胞的体外侵袭能力。

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>Background: The proteasome exists in all eukaryotic cells and provides the main route of intracellular proteins degradation involved in cell growth and apoptosis. Proteasome inhibition could block protein degradation pathways and disturb regulatory networks, possibly leading to profound effects on cell growth, particularly in cancer cells. A proteasome inhibitor with an appropriate toxicity index for malignant cells rather than normal cells would be an attractive anticancer therapy. Methods: The human osteosarcoma (OS) cell lines MG-63 and Saos-2 and normal osteoblast cells were used to study the antitumour activity of the proteasome inhibitor MLN9708/2238. Results: MLN2238 inhibited cell growth, induced cell cycle arrest and apoptosis, and attenuated the invasion abilities of MG-63 and Saos-2 cells, with little cytotoxicity to normal cells. In addition, MLN2238 promoted antitumour mechanisms including the accumulation of E2F1, P53, P21 and other negative G2/M checkpoint proteins; up-regulated the relative expression ratio of BAX/BCL-2, APAF-1 and pro-apoptotic proteins of the BCL-2 family; triggered mitochondrial outer membrane permeabilization (MOMP); down-regulated BCL-2 and XIAP; activated caspase3/8/9; and suppressed MMP2/9 expression and secretion levels. Conclusions: The proteasome may be a novel biochemical target for OS treatment in vitro. Our study provides a promising mechanistic framework for MLN9708/2238 in OS treatment, supporting its clinical development.
机译：> 背景： 蛋白酶体存在于所有真核细胞中，并提供了参与细胞生长和凋亡的细胞内蛋白质降解的主要途径。蛋白酶体抑制作用可能会阻止蛋白质降解途径并干扰调节网络，可能对细胞生长产生深远影响，尤其是在癌细胞中。对恶性细胞而非正常细胞具有适当毒性指标的蛋白酶体抑制剂将是有吸引力的抗癌治疗方法。 方法： 使用人类骨肉瘤（OS）细胞MG-63和Saos-2细胞以及正常的成骨细胞来研究蛋白酶体抑制剂MLN9708 / 2238的抗肿瘤活性。 结果： MLN2238抑制细胞生长，诱导细胞周期停滞和凋亡，并减弱MG-63和Saos-2细胞的侵袭能力，对正常细胞的细胞毒性很小。此外，MLN2238促进了抗肿瘤机制，包括E2F1，P53，P21和其他阴性G2 / M检查点蛋白的积累。上调BAX / BCL-2，APAF-1和BCL-2家族促凋亡蛋白的相对表达率;触发线粒体外膜通透性（MOMP）;下调BCL-2和XIAP;激活的caspase3 / 8/9;并抑制了MMP2 / 9的表达和分泌水平。 结论： 蛋白酶体可能是体外的OS治疗的新型生化靶标。我们的研究为MLN9708 / 2238在OS治疗中提供了有希望的机制框架，支持其临床开发。

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