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Trifluoperazine induces cellular apoptosis by inhibiting autophagy and targeting NUPR1 in multiple myeloma.
FEBS Open Bio ( IF 2.8 ) Pub Date : 2020-08-18 , DOI: 10.1002/2211-5463.12960
Anmao Li 1 , Xuanxin Chen 1 , Zizi Jing 1 , Jianbin Chen 1
Affiliation  

Multiple myeloma (MM) is the second most common hematologic malignancy of immunoglobulin‐secreting plasma cells. Recent modern combination therapies have improved survival rates, but many patients develop resistance to novel drugs, leading to relapse. Trifluoperazine (TFP), a typical antipsychotic drug, has been reported to exert antitumor effects by targeting various pathways. Thus far, the role of TFP in MM has not been elucidated. In the current study, we demonstrated that TFP inhibited cell growth and autophagy activity but induced apoptosis of U266 and RPMI 8226 MM cells. Furthermore, cotreatment of these cell lines with TFP and rapamycin, a potent autophagy inducer, reduced cell apoptosis compared with TFP treatment alone. We also found that TFP inhibited nuclear protein 1 (NUPR1) expression. In the presence of TFP, cells stably overexpressing NUPR1 showed a higher viability than cells treated with the nonspecific control. Autophagy suppression and apoptosis induction caused by TFP were also reversed in MM cells upon NUPR1 overexpression. Overall, our results indicate that in the context of MM, TFP targets NUPR1, inhibiting cell growth and inducing apoptosis by autophagy inhibition. Our results could contribute toward efforts for the development of more effective therapies for MM to be tested in future clinical trials.

中文翻译:

Trifluoperazine 通过抑制自噬和靶向多发性骨髓瘤中的 NUPR1 诱导细胞凋亡。

多发性骨髓瘤 (MM) 是分泌免疫球蛋白的浆细胞的第二常见的血液系统恶性肿瘤。最近的现代联合疗法提高了生存率,但许多患者对新药产生耐药性,导致复发。三氟拉嗪 (TFP) 是一种典型的抗精神病药物,据报道通过靶向多种途径发挥抗肿瘤作用。迄今为止,尚未阐明 TFP 在 MM 中的作用。在目前的研究中,我们证明 TFP 抑制细胞生长和自噬活性,但诱导 U266 和 RPMI 8226 MM 细胞凋亡。此外,与单独使用 TFP 处理相比,用 TFP 和雷帕霉素(一种有效的自噬诱导剂)共同处理这些细胞系可减少细胞凋亡。我们还发现 TFP 抑制核蛋白 1 (NUPR1) 的表达。在 TFP 存在的情况下,稳定过表达 NUPR1 的细胞显示出比用非特异性对照处理的细胞更高的活力。在 NUPR1 过表达后,MM 细胞中由 TFP 引起的自噬抑制和细胞凋亡诱导也被逆转。总体而言,我们的结果表明,在 MM 的情况下,TFP 靶向 NUPR1,抑制细胞生长并通过自噬抑制诱导细胞凋亡。我们的研究结果可能有助于开发更有效的 MM 疗法,以便在未来的临床试验中进行测试。
更新日期:2020-10-02
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