PINK1-Dependent Mitophagy Regulates the Migration and Homing of Multiple Myeloma Cells via the MOB1B-Mediated Hippo-YAP/TAZ Pathway.,Advanced Science

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PINK1-Dependent Mitophagy Regulates the Migration and Homing of Multiple Myeloma Cells via the MOB1B-Mediated Hippo-YAP/TAZ Pathway.
Advanced Science ( IF 14.3 ) Pub Date : 2020-01-23 , DOI: 10.1002/advs.201900860
Shengjun Fan ₁ , Trevor Price ₁ , Wei Huang ₁ , Michelle Plue ₂ , Jonathan Warren ₃ , Pasupathi Sundaramoorthy ₁ , Barry Paul ₁ , Daniel Feinberg ₁ , Nancie MacIver ₃ , Nelson Chao ₁ , Dorothy Sipkins ₁ , Yubin Kang ₁

Affiliation

The roles of mitochondrial dysfunction in carcinogenesis remain largely unknown. The effects of PTEN-induced putative kinase 1 (PINK1)-dependent mitophagy on the pathogenesis of multiple myeloma (MM) are determined. The levels of the PINK1-dependent mitophagy markers PINK1 and parkin RBR E3 ubiquitin protein ligase (PARK2) in CD138+ plasma cells are reduced in patients with MM and correlate with clinical outcomes in myeloma patients. Moreover, the induction of PINK1-dependent mitophagy with carbonylcyanide-m-chlorophenylhydrazone (CCCP) or salinomycin, or overexpression of PINK1 leads to inhibition of transwell migration, suppression of myeloma cell homing to calvarium, and decreased osteolytic bone lesions. Furthermore, genetic deletion of pink1 accelerates myeloma development in a spontaneous X-box binding protein-1 spliced isoform (XBP-1s) transgenic myeloma mouse model and in VK*MYC transplantable myeloma recipient mice. Additionally, treatment with salinomycin shows significant antimyeloma activities in vivo in murine myeloma xenograft models. Finally, the effects of PINK1-dependent mitophagy on myeloma pathogenesis are driven by the activation of the Mps one binder kinase activator (MOB1B)-mediated Hippo pathway and the subsequent downregulation of Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) expression. These data provide direct evidence that PINK1-dependent mitophagy plays a critical role in the pathogenesis of MM and is a potential therapeutic target.

中文翻译：

PINK1 依赖性线粒体自噬通过 MOB1B 介导的 Hippo-YAP/TAZ 途径调节多发性骨髓瘤细胞的迁移和归巢。

线粒体功能障碍在致癌过程中的作用仍然很大程度上未知。确定了 PTEN 诱导的推定激酶 1 (PINK1) 依赖性线粒体自噬对多发性骨髓瘤 (MM) 发病机制的影响。 CD138+ 浆细胞中 PINK1 依赖性线粒体自噬标记物 PINK1 和 Parkin RBR E3 泛素蛋白连接酶 (PARK2) 的水平在 MM 患者中降低，并且与骨髓瘤患者的临床结果相关。此外，用羰基氰间氯苯腙 (CCCP) 或盐霉素诱导 PINK1 依赖性线粒体自噬，或过度表达 PINK1，可抑制 Transwell 迁移，抑制骨髓瘤细胞归巢至颅骨，并减少溶骨性骨病变。此外，pink1 的基因缺失会加速自发 X-box 结合蛋白 1 剪接异构体 (XBP-1s) 转基因骨髓瘤小鼠模型和 VK*MYC 可移植骨髓瘤受体小鼠的骨髓瘤发展。此外，用盐霉素治疗在小鼠骨髓瘤异种移植模型中显示出显着的体内抗骨髓瘤活性。最后，PINK1 依赖性线粒体自噬对骨髓瘤发病机制的影响是由 Mps 1 结合激酶激活剂 (MOB1B) 介导的 Hippo 通路的激活以及随后的 Yes 相关蛋白 (YAP)/转录共激活剂与 PDZ 的下调驱动的。 -结合基序（TAZ）表达。这些数据提供了直接证据，表明 PINK1 依赖性线粒体自噬在 MM 发病机制中发挥着关键作用，并且是潜在的治疗靶点。

更新日期：2020-01-23

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