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二脂胺脱酶 (DLD) 是博特佐米的一个新型分子标

Yu Feng¹, Hongmei Luo¹, Jingcao Huang¹

¹Department of Hematology/Institute of Hematology, West China Hospital, Sichuan University, Chengdu, China.

Cell death & disease

|August 13, 2024

概括

蛋白质酶抑制剂是多发性骨髓瘤 (MM) 的关键. 研究人员发现二脂胺脱酶 (DLD) 是博特佐米布的标,抑制DLD可能会提高MM治疗的敏感性.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
生物化学生物化学

背景情况:

蛋白质酶抑制剂 (PI),如博尔特佐米布,是标准的多发性骨髓瘤 (MM) 治疗方法.
了解博特佐米布的分子点对于改善MM治疗至关重要.

研究的目的:

在MM细胞中识别博特佐米布的新分子标.
调查二脂胺脱酶 (DLD) 在MM病变发生中的作用及其与博特佐米布的相互作用.

主要方法:

在MM细胞中使用生物化学分析研究了博特佐米布相互作用体.
评估了DLD的酶功能及其在NADH生产中的作用.
利用DLD-KD (DLD-KD) 的MM细胞来评估蛋白酶体活性和博特佐米布的敏感性.
检查了DLD表达和MM患者预后之间的相关性.
在体外和体内评估了DLD抑制剂 (CPI-613) 与博特佐米布的联合治疗.

主要成果:

确定了二利胺脱酶 (DLD) 作为MM细胞中博特佐米布的直接分子标.
博特佐米布抑制了DLD的酶活性,导致MM细胞中的NADH水平降低.
DLD knockdown 降低了 NADH,抑制了蛋白质酶组合,降低了基底蛋白质酶活性,并增加了博特佐米布的敏感性.
高DLD表达与MM患者的预后较差相关.
DLD 抑制剂 CPI-613 证明了与博特佐米布的协同抗MM效应.

结论:

二脂胺脱酶 (DLD) 是多发性骨髓瘤中博特佐米布的一个新型分子标.
向DLD可能是一个可行的策略,以提高蛋白酶体抑制剂在MM治疗中的疗效.

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