Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
Department of Blood Transfusion, The Third Xiangya Hospital of Central South University, Changsha, 410013, China.
Chem Biol Interact. 2023 Oct 1;384:110687. doi: 10.1016/j.cbi.2023.110687. Epub 2023 Aug 31.
The activating protein-1 (AP-1) transcription factors (TFs) have been associated with many different cancer types and are promising therapeutic targets in logical malignancies. However, the mechanisms of their role in multiple myeloma (MM) remain elusive. The present study determined and compared the mRNA and protein expression levels of the AP-1 family member JunB in CD138 mononuclear cells from MM patients and healthy donors. Herein, we investigated the effect of T-5224, an inhibitor of JUN/AP-1, on MM. We found that the cytotoxicity of T-5224 toward myeloma is due to its ability to induce cell apoptosis, inhibit proliferation, and induce cell cycle arrest by increasing the levels of cleaved caspase3/7 and concomitantly inhibiting the IRF4/MYC axis. We also noticed that siJunB-mediated deletion of JunB/AP-1 enhanced MM cell apoptosis and affected cell proliferation. The software PROMO was used in the present study to predict the AP-1 TF that may bind the promoter region of IRF4. We confirmed the correlation between JunB/AP-1 and IRF4. Given that bortezomib (BTZ) facilitates IRF4 degradation in MM cells, we applied combination treatment of BTZ with T-5224. T-5224 and BTZ exerted synergistic effects, and T-5224 reversed the effect of BTZ on CD138 primary resistance in MM cells, in part due to suppression of the IRF4/MYC axis. Our results suggest that targeting AP-1 TFs is a promising therapeutic strategy for MM. Additionally, targeting both AP-1 and IRF4 with T-5224 may be a synergistic therapeutic strategy for this clinically challenging subset of MM.
激活蛋白-1 (AP-1) 转录因子 (TFs) 与许多不同类型的癌症相关，是逻辑恶性肿瘤中有前途的治疗靶点。然而，它们在多发性骨髓瘤 (MM) 中的作用机制仍不清楚。本研究测定并比较了 MM 患者和健康供体 CD138 单核细胞中 AP-1 家族成员 JunB 的 mRNA 和蛋白表达水平。在此，我们研究了 JUN/AP-1 抑制剂 T-5224 对 MM 的影响。我们发现 T-5224 对骨髓瘤的细胞毒性是由于其诱导细胞凋亡、抑制增殖和通过增加 cleaved caspase3/7 的水平并同时抑制 IRF4/MYC 轴而诱导细胞周期停滞的能力。我们还注意到，siJunB 介导的 JunB/AP-1 缺失增强了 MM 细胞凋亡并影响了细胞增殖。本研究使用 PROMO 软件预测可能与 IRF4 启动子区域结合的 AP-1 TF。我们证实了 JunB/AP-1 与 IRF4 之间的相关性。鉴于硼替佐米 (BTZ) 促进 MM 细胞中 IRF4 的降解，我们应用 BTZ 与 T-5224 的联合治疗。T-5224 和 BTZ 发挥协同作用，T-5224 部分逆转了 BTZ 对 MM 细胞 CD138 原发性耐药的作用，这部分是由于抑制了 IRF4/MYC 轴。我们的结果表明，靶向 AP-1 TFs 是治疗 MM 的一种有前途的治疗策略。此外，用 T-5224 靶向 AP-1 和 IRF4 可能是治疗这种临床上具有挑战性的 MM 亚群的协同治疗策略。
