Inhibition of Sphingosine Kinase 2 Results in PARK2-Mediated Mitophagy and Induces Apoptosis in Multiple Myeloma

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.

 

Comments：

The study suggests that SK2 plays an important role in regulating mitophagy and apoptosis in multiple myeloma cell lines. Specifically, downregulation of SK2 or treatment with the specific inhibitor ABC294640 induced mitophagy and apoptosis, and this process appears to occur through the SET/PP2AC/PARK2 pathway.

The study suggests that inhibiting PP2AC activity may rescue the process of mitophagy induction, and PP2AC and PARK2 may regulate mitophagy through protein-protein interactions.

Overall, this study provides new insights into the mechanism of mitophagy in multiple myeloma and suggests that targeting SK2 and its downstream pathways may be a potential therapeutic strategy for this disease.

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Cat.No.	Product Name	Information
S7174	Opaganib (ABC294640)	Opaganib (ABC294640) is an orally bioavailable and selective sphingosine kinase-2 (SphK2) inhibitor with IC50 of approximately 60 μM. Phase 1/2.

Related Targets

SPHK