Department of Hematology, The Second Hospital of Shandong University, Jinan, Shandong, China; Shengli Oilfield Central Hospital, Dongying 257034, China.
Department of Hematology, The Second Hospital of Shandong University, Jinan, Shandong, China; Institute of Biotherapy for Hematological Malignancy, Shandong University, Jinan, Shandong, China; Shandong University-Karolinska Institute Collaboration Laboratory for Stem Cell Research, Jinan, Shandong, China.
Int Immunopharmacol. 2024 Nov 15;141:112950. doi: 10.1016/j.intimp.2024.112950. Epub 2024 Aug 18.
Multiple myeloma (MM) is an incurable plasma cell malignancy that has prompted investigations into new potential therapeutic avenues. Epigallocatechin-3-gallate (EGCG), a major component of green tea, confers antioxidant, anti-inflammatory, and anti-tumor properties. Previous studies have shown that EGCG inhibits proliferation and induces apoptosis of multiple myeloma cells, however its underlying molecular mechanisms are largely unknown. In this study, we accordingly sought to examine the therapeutic effects and underlying mechanisms of EGCG on MM. Initially, using CCK8 (Cell Counting Kit-8) assays and Annexin V-FITC/PI staining, we demonstrated that EGCG dose-dependently reduced cell viability and induced apoptosis in the MM cell lines MM.1S and RPMI 8226. Subsequently, mRNA sequencing of EGCG-treated MM.1S cells revealed a significant upregulation of genes associated with endoplasmic reticulum stress (ERS), including P-eIF2α (phosphorylation-eukaryotic translation initiation factor 2 alpha), ATF4 (activating transcription factor 4), CHOP (C/EBP homologous protein, DDIT3), and PUMA (p53 upregulated modulator of apoptosis, BBC3), which were confirmed at the protein level by western blotting. Furthermore, treatment with the eIF2α inhibitor ISRIB reduced the rates of EGCG-induced apoptosis and promoted increases in the protein expression of all four ER stress-related molecules in MM cells. Additionally, mRNA-seq data revealed a downregulation of α-Tubulin 1b (TUBA1B) expression in EGCG-treated MM cells, which was confirmed by western blotting and immunofluorescence analyses. Moreover, we utilized a mouse model to show that EGCG inhibited myeloma tumor growth, which was inhibited by ISRIB. In summary, the findings of this novel study indicated that EGCG promotes apoptosis of MM cells, both via activation of the ER stress pathway and disruption of cytoskeletal integrity. These findings highlight the multi-faceted anti-tumor effects of EGCG and its potential clinical application in MM treatment.
多发性骨髓瘤（MM）是一种不可治愈的浆细胞恶性肿瘤，促使人们探索新的潜在治疗途径。表没食子儿茶素没食子酸酯（EGCG）是绿茶的主要成分，具有抗氧化、抗炎和抗肿瘤特性。先前的研究表明，EGCG 抑制多发性骨髓瘤细胞的增殖并诱导其凋亡，但其潜在的分子机制在很大程度上尚不清楚。在这项研究中，我们因此研究了 EGCG 对 MM 的治疗作用及其潜在机制。首先，我们通过 CCK8（细胞计数试剂盒-8）检测和 Annexin V-FITC/PI 染色实验，证明 EGCG 呈剂量依赖性地降低 MM 细胞系 MM.1S 和 RPMI 8226 的细胞活力并诱导其凋亡。随后，EGCG 处理的 MM.1S 细胞的 mRNA 测序显示，与内质网应激（ERS）相关的基因显著上调，包括 P-eIF2α（磷酸化真核翻译起始因子 2α）、ATF4（激活转录因子 4）、CHOP（C/EBP 同源蛋白，DDIT3）和 PUMA（p53 上调凋亡调节剂，BBC3），Western blot 实验证实了这一点。此外，用 eIF2α 抑制剂 ISRIB 处理可降低 EGCG 诱导的细胞凋亡率，并促进 MM 细胞中这四种与 ER 应激相关分子的蛋白表达增加。此外，mRNA-seq 数据显示 EGCG 处理的 MM 细胞中α-微管蛋白 1b（TUBA1B）的表达下调，Western blot 和免疫荧光分析证实了这一点。此外，我们利用小鼠模型表明 EGCG 抑制骨髓瘤肿瘤生长，而 ISRIB 则抑制了 EGCG 的作用。综上所述，这项新研究的结果表明，EGCG 通过激活内质网应激途径和破坏细胞骨架完整性促进 MM 细胞凋亡。这些发现强调了 EGCG 的多方面抗肿瘤作用及其在 MM 治疗中的潜在临床应用。
