De novo-synthesized ceramide is involved in cannabinoid-induced apoptosis

Pulgar, Teresa Gómez del; Velasco, Guillermo; Sánchez, Cristina; Haro, Amador; Guzmán, Manuel

doi:10.1042/0264-6021:3630183

Cited by 161 publications

(121 citation statements)

References 46 publications

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“…This screen allowed us to identify 2 short membrane proteins that, by a variety of criteria, appear to be the functional orthologs of yeast Tsc3p. Although SPT activity is apparently not highly regulated, a variety of stimuli have been reported to modulate activity a few fold without altering the levels of the LCB1 or LCB2 mRNAs or proteins (20)(21)(22). While it is possible that the ssSPTs contribute to regulation of enzyme activity, given the observation that all 3 proteins copurify it seems more likely that they are integral subunits of the SPT holoenzymes, a conclusion entirely consistent with the extremely small increase in SPT activity observed when the hLCB1 and hLCB2 subunits are overexpressed by themselves.…”

Section: Discussionmentioning

confidence: 99%

Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities

Han¹,

Gupta²,

Gable³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

238

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Serine palmitoyltransferase (SPT) catalyzes the first committed step in sphingolipid biosynthesis. In yeast, SPT is composed of a heterodimer of 2 highly-related subunits, Lcb1p and Lcb2p, and a third subunit, Tsc3p, which increases enzyme activity markedly and is required for growth at elevated temperatures. Higher eukaryotic orthologs of Lcb1p and Lcb2p have been identified, but SPT activity is not highly correlated with coexpression of these subunits and no ortholog of Tsc3p has been identified. Here, we report the discovery of 2 proteins, ssSPTa and ssSPTb, which despite sharing no homology with Tsc3p, each substantially enhance the activity of mammalian SPT expressed in either yeast or mammalian cells and therefore define an evolutionarily conserved family of low molecular weight proteins that confer full enzyme activity. The 2 ssSPT isoforms share a conserved hydrophobic central domain predicted to reside in the membrane, and each interacts with both hLCB1 and hLCB2 as assessed by positive split ubiquitin 2-hybrid analysis. The presence of these small subunits, along with 2 hLCB2 isofoms, suggests that there are 4 distinct human SPT isozymes. When each SPT isozyme was expressed in either yeast or CHO LyB cells lacking endogenous SPT activity, characterization of their in vitro enzymatic activities, and long-chain base (LCB) profiling revealed differences in acyl-CoA preference that offer a potential explanation for the observed diversity of LCB seen in mammalian cells.

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Section: Discussionmentioning

confidence: 99%

Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities

Han¹,

Gupta²,

Gable³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

238

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“…This pathway can be metabolically induced in response to metabolic loading with either serine or palmitate [11]. It is also activated by chemotherapeutic agents [8], heat stress [5], oxidized LDL [12], and cannabinoids [13]. Studies have implicated the ceramide formed de novo in mediating some of the effects of these inducers on stress responses, and apoptosis [5,8,13].…”

Section: Introductionmentioning

confidence: 99%

The sphingolipid salvage pathway in ceramide metabolism and signaling

Kitatani

Idkowiak‐Baldys

Hannun

2008

Cellular Signalling

527

457

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Sphingolipids are important components of eukaryotic cells, many of which function as bioactive signaling molecules. Of these, ceramide is a central metabolite and plays key roles in a variety of cellular responses, including regulation of cell growth, viability, differentiation, and senescence. Ceramide is composed of the long-chain sphingoid base, sphingosine, in N-linkage to a variety of acyl groups. Sphingosine serves as the product of sphingolipid catabolism, and it is mostly salvaged through re-acylation, resulting in the generation of ceramide or its derivatives. This recycling of sphingosine is termed the "salvage pathway", and recent evidence points to important roles for this pathway in ceramide metabolism and function. A number of enzymes are involved in the salvage pathway, and these include sphingomyelinases, cerebrosidases, ceramidases, and ceramide synthases. Recent studies suggest that the salvage pathway is not only subject to regulation, but it also modulates the formation of ceramide and subsequent ceramide-dependent cellular signals. This review focuses on the salvage pathway in ceramide metabolism, its regulation, its experimental analysis, and emerging biological functions.

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“…One of the primary events after cannabinoid treatment is a sustained de novo synthesis of the lipid second messenger ceramide, which in turn is followed by inhibition of AKT signaling (15). Strikingly, both of these signaling events mark a major difference between tumor cells and healthy nontransformed cells, which undergo AKT activation without de novo synthesis of ceramide after cannabinoid stimulation (16).…”

Section: Introductionmentioning

confidence: 99%

Cannabinoid receptor 1 is a potential drug target for treatment of translocation-positive rhabdomyosarcoma

Oesch

Walter

Wachtel

et al. 2009

Molecular Cancer Therapeutics

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Gene expression profiling has revealed that the gene coding for cannabinoid receptor 1 (CB1) is highly up-regulated in rhabdomyosarcoma biopsies bearing the typical chromosomal translocations PAX3/FKHR or PAX7/FKHR. Because cannabinoid receptor agonists are capable of reducing proliferation and inducing apoptosis in diverse cancer cells such as glioma, breast cancer, and melanoma, we evaluated whether CB1 is a potential drug target in rhabdomyosarcoma. Our study shows that treatment with the cannabinoid receptor agonists HU210 and Δ 9 -tetrahydrocannabinol lowers the viability of translocationpositive rhabdomyosarcoma cells through the induction of apoptosis. This effect relies on inhibition of AKT signaling and induction of the stress-associated transcription factor p8 because small interfering RNA-mediated down-regulation of p8 rescued cell viability upon cannabinoid treatment. Finally, treatment of xenografts with HU210 led to a significant suppression of tumor growth in vivo. These results support the notion that cannabinoid receptor agonists could represent a novel targeted approach for treatment of translocation-positive rhabdomyosarcoma.

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De novo-synthesized ceramide is involved in cannabinoid-induced apoptosis

Cited by 161 publications

References 46 publications

Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities

Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities

The sphingolipid salvage pathway in ceramide metabolism and signaling

Cannabinoid receptor 1 is a potential drug target for treatment of translocation-positive rhabdomyosarcoma

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