The First School of Clinical Medicine of Lanzhou University, Department of Orthopaedics, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu, China.
Department of Orthopaedics, Gansu Provincial Hospital, Lanzhou 730000, Gansu, China.
Aging (Albany NY). 2022 Mar 25;14(6):2793-2804. doi: 10.18632/aging.203975.
Osteosarcoma is the most prevalent bone cancer and accounts for over half of sarcomas. In this study, we identified that the treatment of levobupivacaine suppressed proliferation of osteosarcoma cells . The tumor xenograft analysis showed that levobupivacaine significantly repressed the osteosarcoma cell growth in the nude mice. The treatment of levobupivacaine improved the apoptosis rate and attenuated invasion and migration abilities of osteosarcoma cells. The sphere formation capabilities of osteosarcoma cells were repressed by levobupivacaine. The protein levels of Sox-2, Oct3/4, and Nanog were inhibited by the treatment of levobupivacaine in osteosarcoma cells. Regarding mechanism, we identified that levobupivacaine inhibited MAFB and KAT5 expression in osteosarcoma cells. We observed that lysine acetyltransferase 5 could enriched in the promoter region of MAF BZIP transcription factor B, while levobupivacaine treatment could repressed the enrichment. The suppression of KAT5 by siRNA repressed the enrichment of histone H3 acetylation at lysine 27 and RNA polymerase II on promoter of MAFB. The expression of MAFB was decreased by KAT5 knockdown in osteosarcoma cells. The expression of MAFB was repressed by levobupivacaine, while the overexpression of KAT5 could reverse the repression of MAFB. KAT5 contributes to the cell proliferation and stemness of osteosarcoma cells. The overexpression of KAT5 or MAFB could reverse levobupivacaine-attenuated cell proliferation and stemness of osteosarcoma cells. Therefore, we concluded that local anesthetic levobupivacaine inhibited stemness of osteosarcoma cells by epigenetically repressing MAFB though reducing KAT5 expression. Levobupivacaine may act as a potential therapeutic candidate for osteosarcoma by targeting cancer stem cells.
骨肉瘤是最常见的骨癌，占肉瘤的一半以上。在这项研究中，我们发现布比卡因的治疗抑制了骨肉瘤细胞的增殖。肿瘤异种移植分析表明，布比卡因显著抑制了裸鼠中骨肉瘤细胞的生长。布比卡因的治疗提高了骨肉瘤细胞的凋亡率，并减弱了其侵袭和迁移能力。布比卡因抑制了骨肉瘤细胞的球体形成能力。布比卡因处理抑制了骨肉瘤细胞中 Sox-2、Oct3/4 和 Nanog 的蛋白水平。在机制方面，我们发现布比卡因抑制了骨肉瘤细胞中 MAFB 和 KAT5 的表达。我们观察到赖氨酸乙酰转移酶 5 可以富集在 MAF BZIP 转录因子 B 的启动子区域，而布比卡因处理可以抑制其富集。siRNA 敲低 KAT5 抑制了组蛋白 H3 赖氨酸 27 乙酰化和 RNA 聚合酶 II 在 MAFB 启动子上的富集。在骨肉瘤细胞中，KAT5 敲低降低了 MAFB 的表达。布比卡因抑制了 MAFB 的表达，而过表达 KAT5 可以逆转 MAFB 的抑制。KAT5 促进了骨肉瘤细胞的增殖和干细胞特性。在骨肉瘤细胞中，KAT5 或 MAFB 的过表达可以逆转布比卡因减弱的细胞增殖和干细胞特性。因此，我们得出结论，局部麻醉剂布比卡因通过降低 KAT5 的表达，抑制 MAFB 的表观遗传抑制，抑制骨肉瘤细胞的干性。布比卡因可能通过靶向肿瘤干细胞成为治疗骨肉瘤的潜在候选药物。
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