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

Abstract

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.

Astaxanthin Inhibits H2O2-Induced Excessive Mitophagy and Apoptosis in SH-SY5Y Cells by Regulation of Akt/mTOR Activation

“…The PINK1/Parkin pathway promotes the selective degradation of damaged mitochondria via mitophagy [7]. Emerging evidence has supported that mitophagy plays a double-edged role in responses to exogenous stressors, contributing to both the protection of cellular homeostasis and the induction of cell death [52,53]. Oxidative stress has been found to induce mitophagy and apoptosis [54].…”

“…Oxidative stress has been found to induce mitophagy and apoptosis [54]. It has been shown that mitophagy is involved in apoptotic stress responses and promotes apoptosis [53]. Apoptosis can be triggered in vari-ous human cells by the overexpression of Parkin or the enhancement of the ubiquitylation effect of Parkin, which can cause the excessive removal of mitochondria [14,15].…”

“…edged role in responses to exogenous stressors, contributing to both the protection of cellular homeostasis and the induction of cell death [52,53]. Oxidative stress has been found to induce mitophagy and apoptosis [54].…”

Natural Products and Small Molecules Targeting Cellular Ceramide Metabolism to Enhance Apoptosis in Cancer Cells

“…ABC294640 was the first SK2 inhibitor, and when utilizing this as a biological probe, several outcomes were reported in terms of S1P-mediated signaling. For example, mitophagy-mediated apoptosis was unraveled in a multiple myeloma cell line [ 71 ]. Other inhibitors, namely SG-12 [ 72 ], ®-FTY720-OMe [ 73 ], K145 [ 74 ], and VT-ME6 [ 75 ] exhibited optimal potency and selectivity.…”