Department of Orthopaedic Surgery, Faculty of Medicine, Oita University, Oita, 879-5593, Japan.
Oncol Res. 2023 Jul 21;31(5):631-643. doi: 10.32604/or.2023.029745. eCollection 2023.
Heat shock protein (HSP) 90 plays a crucial role in correcting the misfolded three-dimensional structure of proteins, assisting them in folding into proper conformations. HSP90 is critical in maintaining the normal functions of various proteins within cells, as essential factors for cellular homeostasis. Contrastingly, HSP90 simultaneously supports the maturation of cancer-related proteins, including mesenchymal epithelial transition factor (MET) within tumor cells. All osteosarcoma cell lines had elevated MET expression in the cDNA array in our possession. MET, a tyrosine kinase receptor, promotes proliferation and an anti-apoptotic state through the activation of the MET pathway constructed by HSP90. In this study, we treated osteosarcoma cells with an HSP90 inhibitor, 17-demethoxygeldanamycin hydrochloride (17-DMAG), and assessed the changes in the MET signaling pathway and also the antitumor effect of the drug. The cell cycle in osteosarcoma cells administered 17-DMAG was found to be halted at the G2/M phase. Additionally, treatment with 17-DMAG inhibited cell proliferation and induced apoptosis. Inhibition of tumor cell proliferation was also observed in an model system, mice that were treated with 17-DMAG. Based on the results of this study, we were able to confirm that 17-DMAG promotes inhibition of osteosarcoma cell proliferation and induction of apoptosis by inhibition of MET, a protein highly expressed in osteosarcoma cells. This approach may be useful for the establishment of a new treatment strategy for patients resistant to the standard treatment for osteosarcoma.
热休克蛋白（HSP）90 在纠正蛋白质错误折叠的三维结构方面发挥着关键作用，协助它们折叠成适当的构象。HSP90 对于维持细胞内各种蛋白质的正常功能至关重要，是细胞内稳态的关键因素。相比之下，HSP90 同时支持肿瘤细胞内与癌症相关的蛋白质的成熟，包括间质上皮转化因子（MET）。我们拥有的 cDNA 阵列中，所有骨肉瘤细胞系的 MET 表达均升高。MET 是一种酪氨酸激酶受体，通过 HSP90 构建的 MET 途径的激活，促进增殖和抗凋亡状态。在这项研究中，我们用 HSP90 抑制剂 17-去甲氧基格尔德霉素盐酸盐（17-DMAG）处理骨肉瘤细胞，评估 MET 信号通路的变化以及药物的抗肿瘤作用。17-DMAG 处理的骨肉瘤细胞的细胞周期停滞在 G2/M 期。此外，用 17-DMAG 处理还抑制了细胞增殖并诱导了细胞凋亡。在 17-DMAG 处理的模型系统中也观察到肿瘤细胞增殖的抑制。根据这项研究的结果，我们能够证实 17-DMAG 通过抑制骨肉瘤细胞中高度表达的 MET 来促进骨肉瘤细胞增殖的抑制和凋亡的诱导。这种方法可能有助于为对骨肉瘤标准治疗有耐药性的患者建立新的治疗策略。
