DUT enhances drug resistance to proteasome inhibitors via promoting mitochondrial function in multiple myeloma
DUT enhances drug resistance to proteasome inhibitors via promoting mitochondrial function in multiple myeloma
复制标题
DOI：
10.1093/carcin/bgac071
复制
发表时间：
2022-11-25
期刊：
影响因子：
4.7
通讯作者：
Li，Qian
中科院分区：
文献类型：
--
作者：
Wang，Yafei;Gao，Shuang;Li，Qian
对蛋白酶体抑制剂（PI）如硼替佐米（BTZ）的获得性耐药已成为多发性骨髓瘤（MM）临床治疗中的一个棘手障碍，但其机制尚未完全阐明。在本研究中，我们建立了硼替佐米耐药（BR）骨髓瘤细胞，并进行了稳定同位素标记的氨基酸在细胞培养（SILAC）分析筛选蛋白质表达谱。BR MM细胞中核苷酸代谢的重要酶脱氧尿苷三磷酸酶（DUT）水平升高。回顾性分析表明，DUT表达较高的患者对PI治疗的反应和临床结局较差。此外，DUT敲除伴随着增殖细胞核抗原（PCNA）的下调，有助于减缓细胞生长，以及由于硼替佐米治疗增加细胞凋亡。相反，亲本MM. 1 S和LP-1细胞中的DUT过表达增强BTZ抗性。此外，对BTZ的获得性抗性可触发线粒体代谢和功能的调节，如通过与线粒体代谢相关的基因的表达升高以及BR MM细胞中氧消耗速率和三磷酸腺苷（ATP）产生的改变所证明的。DUT抑制部分减弱了线粒体调节，反而有利于BTZ暴露后线粒体完整性的早期损伤，从而限制MM进展并克服体外和体内对BTZ治疗的耐药性。总之，我们揭示了DUT对MM获得性耐药性的先前未被认识的影响，因此操纵DUT可能有效地使MM细胞对PI敏感。
Acquired chemoresistance to proteasome inhibitors (PIs), such as bortezomib (BTZ), becomes an intractable obstacle in the management of multiple myeloma (MM) in the clinic, but the underlying mechanisms are still not well elucidated. In the current study, we established bortezomib-resistant (BR) myeloma cells and performed stable isotope labeling by amino acids in cell culture (SILAC) assay to screen profiled protein expression. The level of deoxyuridine triphosphatase (DUT), an important enzyme of nucleotide metabolism, increased in the BR MM cells. Retrospective analysis indicated patients with higherDUTexpression had poorer responses to PI-based treatment and clinical outcomes.DUTknockdown by RNAi effectively minimized BTZ resistance in MM cells. Moreover, DUT knockdown was accompanied with the downregulation of proliferating cell nuclear antigen (PCNA), contributing to decelerating cell growth, as well as augmented apoptosis due to bortezomib treatment. In contrast, DUT overexpression in parental MM.1S and LP-1 cells enhanced BTZ resistance. Furthermore, acquired resistance to BTZ could trigger the modulation of mitochondrial metabolism and function, as evidenced by elevated expression of genes associated with mitochondrial metabolism, as well as altered oxygen consumption rate and adenosine triphosphate (ATP) production in BR MM cells. DUT inhibition partially attenuated mitochondrial modulation, and instead favored an early impairment of mitochondrial integrity upon BTZ exposure so as to restrict MM progression and overcome drug resistance to BTZ treatment bothin vitroandin vivo. In conclusion, we unveiled previously unrecognized effects of DUT on acquired drug resistance of MM, thus manipulating DUT may be efficacious for sensitizing MM cells to PIs.