A house divided: Ceramide, sphingosine, and sphingosine-1-phosphate in programmed cell death

Abstract

Programmed cell death is an important physiological response to many forms of cellular stress. The signaling cascades that result in programmed cell death are as elaborate as those that promote cell survival, and it is clear that coordination of both protein- and lipid-mediated signals is crucial for proper cell execution. Sphingolipids are a large class of lipids whose diverse members share the common feature of a long-chain sphingoid base, e.g., sphingosine. Many sphingolipids have been shown to play essential roles in both death signaling and survival. Ceramide, an N-acylsphingosine, has been implicated in cell death following a myriad of cellular stresses. Sphingosine itself can induce cell death but via pathways both similar and dissimilar to those of ceramide. Sphingosine-1-phosphate, on the other hand, is an anti-apoptotic molecule that mediates a host of cellular effects antagonistic to those of its pro-apoptotic sphingolipid siblings. Extraordinarily, these lipid mediators are metabolically juxtaposed, suggesting that the regulation of their metabolism is of the utmost importance in determining cell fate. In this review, we briefly examine the role of ceramide, sphingosine, and sphingosine-1-phosphate in programmed cell death and highlight the potential roles that these lipids play in the pathway to apoptosis.

Lipid signalling in disease

“…When 14-3-3 proteins are phosphorylated, they dimerize and release BAD, which permeabilizes the outer mitochondrial membranes (reviewed in REF. 8). From this, it becomes clear that binding of 14-3-3 proteins to phosphorylated PKB/Akt substrates and SDK1 action on 14-3-3 proteins provide an intersection at which increased sphingosine intercepts with a branch of PI3K signalling.…”

Akt2 and acid ceramidase cooperate to induce cell invasion and resistance to apoptosis

“…21 ASAH1 is a ubiquitously expressed enzyme that converts ceramide into sphingosine and free fatty acids. [22][23][24] Ceramide is a major intracellular activator of apoptotic cell death, whereas sphingosine, after its conversion to sphingosine-1-phosphate by sphingosine-1 kinase (SPHK1), stimulates cell growth and proliferation. [22][23][24] SPHK1 is known to activate Akt 25 and is itself subject to activating phosphorylation.…”

“…[22][23][24] Ceramide is a major intracellular activator of apoptotic cell death, whereas sphingosine, after its conversion to sphingosine-1-phosphate by sphingosine-1 kinase (SPHK1), stimulates cell growth and proliferation. [22][23][24] SPHK1 is known to activate Akt 25 and is itself subject to activating phosphorylation. 26 ASAH1 is upregulated in many cancers, particularly prostate cancer, 27 and is believed to have an important role in tumor promotion.…”

Sphingolipids and membrane biology as determined from genetic models

“…According to this model, enzymes that interconvert active sphingolipids act as switches that control the relative levels of each of metabolite, thereby regulating vital cellular processes [21][22][23]. The subsequent identification of genes that encode proteins that catalyze these reactions in yeast, data from genome annotation, and the identification of homologous genes in higher eukaryotes have led to the generation of knock-out transgenic animals.…”