Exercise Promotes Pro-Apoptotic Ceramide Signaling in a Mouse Melanoma Model

SIMPLE SUMMARY: Exercise has been shown to improve the efficacy of chemotherapy against several tumor models using mice through modulating tumor vascular perfusion, immune function, circulating growth factors, hypoxia, and metabolism in tumor cells and their surrounding microenvironment. However, little is known about the effect of exercise on tumor-cell-intrinsic death mechanisms, such as apoptosis. Ceramide is a bioactive lipid that can promote cell death. The strategy of increasing intracellular ceramide has potential as an anticancer treatment for melanoma with dysregulated ceramide metabolism, but there is not yet a clinically relevant method to do so. We found that moderate aerobic exercise increases pro-apoptotic ceramide in melanoma in mice, and activates p53 signaling, promoting tumor cell apoptosis. This finding suggests that exercise may be most effective as an adjuvant therapy to sensitize cancer cells to anticancer treatments in tumors that exhibit downregulated ceramide generation to evade cell death. ABSTRACT: Ceramides are essential sphingolipids that mediate cell death and survival. Low ceramide content in melanoma is one mechanism of drug resistance. Thus, increasing the ceramide content in tumor cells is likely to increase their sensitivity to cytotoxic therapy. Aerobic exercise has been shown to modulate ceramide metabolism in healthy tissue, but the relationship between exercise and ceramide in tumors has not been evaluated. Here, we demonstrate that aerobic exercise causes tumor cell apoptosis and accumulation of pro-apoptotic ceramides in B16F10 but not BP melanoma models using mice. B16F10 tumor-bearing mice were treated with two weeks of moderate treadmill exercise, or were control, unexercised mice. A reverse-phase protein array was used to identify canonical p53 apoptotic signaling as a key pathway upregulated by exercise, and we demonstrate increased apoptosis in tumors from exercised mice. Consistent with this finding, pro-apoptotic C16-ceramide, and the ceramide generating enzyme ceramide synthase 6 (CerS6), were higher in B16F10 tumors from exercised mice, while pro-survival sphingosine kinase 1 (Sphk1) was lower. These data suggest that exercise contributes to B16F10 tumor cell death, possibly by modulating ceramide metabolism toward a pro-apoptotic ceramide/sphingosine-1-phosphate balance. However, these results are not consistent in BP tumors, demonstrating that exercise can have different effects on tumors of different patient or mouse origin with the same diagnosis. This work indicates that exercise might be most effective as a therapeutic adjuvant with therapies that kill tumor cells in a ceramide-dependent manner.