Ceramide Synthase 6 Maximizes p53 Function to Prevent Progeny Formation from Polyploid Giant Cancer Cells

Simple Summary One mechanism that contributes to cancer recurrence is the ability of some malignant cells to temporarily halt cell division and accumulate multiple nuclei that are later released as progeny, which resume cell division. The release of progeny occurs via primitive cleavage and is highly dependent on the sphingolipid enzyme acid ceramidase but the role of sphingolipid metabolism in this process remains to be elucidated. This study highlights differences in sphingolipid metabolism between non-polyploid and polyploid cancer cells and shows that ceramide synthase 6, which preferentially generates C-16-ceramide maximizes the ability of the tumor suppressor p53 to inhibit progeny formation in polyploid cancer cells. These results offer an explanation as to why non-cancerous polyploid cells, which express wildtype p53, do not generate progeny and suggest that cancer cells with deregulated p53 function pose a higher risk of evading therapy especially if enzymes that generate C-16-ceramide are also dysregulated. Polyploid giant cancer cells (PGCC) constitute a transiently senescent subpopulation of cancer cells that arises in response to stress. PGCC are capable of generating progeny via a primitive, cleavage-like cell division that is dependent on the sphingolipid enzyme acid ceramidase (ASAH1). The goal of this study was to understand differences in sphingolipid metabolism between non-polyploid and polyploid cancer cells to gain an understanding of the ASAH1-dependence in the PGCC population. Steady-state and flux analysis of sphingolipids did not support our initial hypothesis that the ASAH1 product sphingosine is rapidly converted into the pro-survival lipid sphingosine-1-phosphate. Instead, our results suggest that ASAH1 activity is important for preventing the accumulation of long chain ceramides such as C-16-ceramide. We therefore determined how modulation of C-16-ceramide, either through CerS6 or p53, a known PGCC suppressor and enhancer of CerS6-derived C-16-ceramide, affected PGCC progeny formation. Co-expression of the CerS6 and p53 abrogated the ability of PGCC to form offspring, suggesting that the two genes form a positive feedback loop. CerS6 enhanced the effect of p53 by significantly increasing protein half-life. Our results support the idea that sphingolipid metabolism is of functional importance in PGCC and that targeting this signaling pathway has potential for clinical intervention.

Automated summary

The study reveals differences in sphingolipid metabolism between non-polyploid and polyploid cancer cells, showing that CerS6 in polyploid cells enhances the ability of the tumor suppressor p53 to inhibit progeny formation. Modulation of C-16-ceramide can prevent polyploid giant cancer cells from generating offspring, and targeting sphingolipid metabolism pathway holds potential for clinical intervention.