Ceramide Signaling and p53 Pathways

Abstract

Ceramides, important players in signal transduction, interact with multiple cellular pathways, including p53 pathways. However, the relationship between ceramide and p53 is very complex, and mechanisms underlying their coregulation are diverse and not fully characterized. The role of p53, an important cellular regulator and a transcription factor, is linked to its tumor suppressor function. Ceramides are involved in the regulation of fundamental processes in cancer cells including cell death, proliferation, autophagy, and drug resistance. This regulation, however, can be pro-death or pro-survival depending on cancer type, the balance between ceramide species, the rate of their synthesis and utilization, and the availability of a specific array of downstream targets. This chapter highlights the central role of ceramide in sphingolipid metabolism, its role in cancer, specific effectors in ceramide pathways controlled by p53, and coregulation of ceramide and p53 signaling. We discuss the recent studies, which underscore the function of p53 in the regulation of ceramide pathways and the reciprocal regulation of p53 by ceramide. This complex relationship is based on several molecular mechanisms including the p53-dependent transcriptional regulation of enzymes in sphingolipid pathways, the activation of mutant p53 through ceramide-mediated alternative splicing, as well as modulation of the p53 function through direct and indirect effects on p53 coregulators and downstream targets. Further insight into the connections between ceramide and p53 will allow simultaneous targeting of the two pathways with a potential to yield more efficient anticancer therapeutics.

Unique Roles of Sphingolipids in Selected Malignant and Nonmalignant Lesions of Female Reproductive System

“…This claim is supported by the fact that the content of all measured sphingolipids, ceramide species, and enzymes catalyzing the transformation to bioactive derivatives was upregulated in the neoplasm tissue. Additionally, the accumulation of sphinganine and dihydroceramide coupled with the activation of palmitoyltransferase suggests that ceramides are synthesized de novo [12, 23–25]. This remains in agreement with other reports that present a remarkably elevated content of dihydroceramide and an increased level of SPT in several types of carcinoma.…”

Oncometabolites in cancer aggressiveness and tumour repopulation

“…Ceramides, which are involved in the modulation of multiple cellular pathways, including cytoskeleton dynamics, endocytosis, protein transport and subcellular localization, the cell cycle, autophagy, and apoptosis, are also present at lower levels in IDH1‐mutant glioma tissues compared to wild‐type (Zhou et al , ). Intriguingly, crosstalk between bioactive lipid metabolites, such as ceramides, and the tumour suppressor p53 has been reported by various studies (Jeffries & Krupenko, ), suggesting a role of oncometabolites in the p53‐mediated modulation of cancer progression. Indeed, C16‐ceramide can bind p53 causing disruption of the p53‐mouse double minute 2 homolog (MDM2) complex and reduction of p53 ubiquitination, thus leading to p53 accumulation as a cellular response to various cellular stresses.…”

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

“…Loss of p53 is important for polyploidy and tumorigenicity but the role of sphingolipids in these processes is unknown [ 25 , 26 , 27 ]. The Krupenko laboratory recently identified a positive feedback loop in which C 16 -ceramide serves as an activator of p53 by stabilizing the protein through direct interaction with the DNA binding domain, and p53 in turn transcriptionally activates CerS6, which preferentially generates C 16 -ceramide [ 28 ]. PPC1, which are derived from PC3 cells, lack p53 protein expression due to loss of one allele and a truncating mutation in the other [ 29 ].…”