Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Curr Oncol. 2023 Mar 4;30(3):3047-3063. doi: 10.3390/curroncol30030231.
Mitophagy plays an important role in maintaining mitochondrial homeostasis by clearing damaged mitochondria. Sphingosine kinase 2 (SK2), a type of sphingosine kinase, is an important metabolic enzyme involved in generating sphingosine-1-phosphate. Its expression level is elevated in many cancers and is associated with poor clinical outcomes. However, the relationship between SK2 and mitochondrial dysfunction remains unclear. We found that the genetic downregulation of SK2 or treatment with ABC294640, a specific inhibitor of SK2, induced mitophagy and apoptosis in multiple myeloma cell lines. We showed that mitophagy correlates with apoptosis induction and likely occurs through the SET/PP2AC/PARK2 pathway, where inhibiting PP2AC activity may rescue this process. Furthermore, we found that PP2AC and PARK2 form a complex, suggesting that they might regulate mitophagy through protein-protein interactions. Our study demonstrates the important role of SK2 in regulating mitophagy and provides new insights into the mechanism of mitophagy in multiple myeloma.
自噬在清除受损线粒体以维持线粒体稳态方面发挥着重要作用。鞘氨醇激酶 2（SK2）是一种鞘氨醇激酶，是生成 1-磷酸鞘氨醇的重要代谢酶。其表达水平在许多癌症中升高，与不良的临床结局相关。然而，SK2 与线粒体功能障碍之间的关系尚不清楚。我们发现，SK2 的基因下调或使用 SK2 的特异性抑制剂 ABC294640 处理可诱导多发性骨髓瘤细胞系发生自噬和细胞凋亡。我们表明，自噬与凋亡诱导相关，可能通过 SET/PP2AC/PARK2 途径发生，抑制 PP2AC 活性可能挽救这一过程。此外，我们发现 PP2AC 和 PARK2 形成复合物，表明它们可能通过蛋白-蛋白相互作用来调节自噬。我们的研究表明 SK2 在调节自噬方面起着重要作用，并为多发性骨髓瘤中自噬的机制提供了新的见解。
