Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
Department of Hematology and Oncology, Soochow University Affiliated Taicang Hospital (the First Peoples Hospital of Taicang), Taicang 215400, China.
Acta Biochim Biophys Sin (Shanghai). 2021 May 21;53(6):775-783. doi: 10.1093/abbs/gmab042.
Resveratrol, a natural compound extracted from the skins of grapes, berries, or other fruits, has been shown to have anti-tumor effects against multiple myeloma (MM) via promoting apoptosis and inhibiting cell viability. In addition to apoptosis, autophagy also plays a significant role in anti-tumor effects. However, whether autophagy is involved in anti-MM activity of resveratrol remains unclear. In this study, human MM cell lines U266, RPMI-8226, and NCI-H929 were treated with resveratrol. Cell Counting Kit-8 assay and colony formation assay were used to measure cell viability. Western blot analysis was used to detect apoptosis- and autophagy-associated proteins. 3-Methyladenine (3-MA) was applied to inhibit autophagy. Results showed that resveratrol inhibited cell viability and colony formation via promoting apoptosis and autophagy in MM cell lines U266, RPMI-8226, and NCI-H929. Resveratrol promoted apoptosis-related proteins, Caspase-3 activating poly-ADP-ribose polymerase and Caspase-3 cleavage, and decreased the protein level of Survivin in a dose-dependent manner. Additionally, resveratrol upregulated the levels of LC3 and Beclin1 in a dose-dependent way, indicating that autophagy might be implicated in anti-MM effect of resveratrol. Furthermore, 3-MA relieved the cytotoxicity of resveratrol by blocking the autophagic flux. Resveratrol increased the phosphorylation of adenosine monophosphate (AMP)-activated protein kinase and decreased the phosphorylation of mammalian target of rapamycin (mTOR) and its downstream substrates p70S6K and 4EBP1 in a dose-dependent manner, leading to autophagy. Therefore, our results suggest that resveratrol exerts anti-MM effects through apoptosis and autophagy, which can be used as a new therapeutic strategy for MM in clinic.
白藜芦醇是一种从葡萄、浆果或其他水果的皮中提取的天然化合物，已被证明通过促进细胞凋亡和抑制细胞活力对多发性骨髓瘤（MM）具有抗肿瘤作用。除了细胞凋亡外，自噬在抗肿瘤作用中也起着重要作用。然而，自噬是否参与白藜芦醇的抗 MM 活性尚不清楚。在这项研究中，用人 MM 细胞系 U266、RPMI-8226 和 NCI-H929 处理白藜芦醇。使用细胞计数试剂盒-8 测定法和集落形成测定法来测量细胞活力。Western blot 分析用于检测凋亡和自噬相关蛋白。3-甲基腺嘌呤（3-MA）用于抑制自噬。结果表明，白藜芦醇通过促进 U266、RPMI-8226 和 NCI-H929 中的细胞凋亡和自噬来抑制细胞活力和集落形成。白藜芦醇以剂量依赖性方式促进凋亡相关蛋白 Caspase-3 激活多聚 ADP-核糖聚合酶和 Caspase-3 切割，并降低 Survivin 的蛋白水平。此外，白藜芦醇以剂量依赖性方式上调 LC3 和 Beclin1 的水平，表明自噬可能参与白藜芦醇的抗 MM 作用。此外，3-MA 通过阻断自噬通量来缓解白藜芦醇的细胞毒性。白藜芦醇以剂量依赖性方式增加 AMP 激活的蛋白激酶的磷酸化，降低哺乳动物雷帕霉素靶蛋白（mTOR）及其下游底物 p70S6K 和 4EBP1 的磷酸化，导致自噬。因此，我们的结果表明，白藜芦醇通过细胞凋亡和自噬发挥抗 MM 作用，可作为 MM 的一种新的临床治疗策略。
