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

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Biochem J. 2002 April 1; 363(Pt 1): 183–188.
PMCID: PMC1222465

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

This article has been cited by other articles in PMC.

ABSTRACT

Delta(9)-Tetrahydrocannabinol (THC) and other cannabinoids have been shown to induce apoptosis of glioma cells via ceramide generation. In the present study, we investigated the metabolic origin of the ceramide responsible for this cannabinoid-induced apoptosis by using two subclones of C6 glioma cells: C6.9, which is sensitive to THC-induced apoptosis; and C6.4, which is resistant to THC-induced apoptosis. Pharmacological inhibition of ceramide synthesis de novo, but not of neutral and acid sphingomyelinases, prevented THC-induced apoptosis in C6.9 cells. The activity of serine palmitoyltransferase (SPT), which catalyses the rate-limiting step of ceramide synthesis de novo, was remarkably enhanced by THC in C6.9 cells, but not in C6.4 cells. However, no major changes in SPT mRNA and protein levels were evident. Changes in SPT activity paralleled changes in ceramide levels. Pharmacological inhibition of ceramide synthesis de novo also prevented the stimulation of extracellular-signal-regulated kinase and the inhibition of protein kinase B triggered by cannabinoids. These findings show that de novo-synthesized ceramide is involved in cannabinoid-induced apoptosis of glioma cells.

FULL TEXT

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De novo-synthesized ceramide is involved in cannabinoid-induced apoptosis
Teresa GOY MEZ DEL PULGAR, Guillermo VELASCO, Cristina SAY NCHEZ, Amador HARO and Manuel GUZMAY N1 Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain

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SELECTED REFERENCES

These references are in PubMed. This may not be the complete list of references from this article.
  • Felder CC, Glass M. Cannabinoid receptors and their endogenous agonists. Annu Rev Pharmacol Toxicol. 1998;38:179–200. [PubMed]
  • Pertwee RG. Cannabinoid receptor ligands: clinical and neuropharmacological considerations, relevant to future drug discovery and development. Expert Opin Investig Drugs. 2000 Jul;9(7):1553–1571. [PubMed]
  • Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990 Aug 9;346(6284):561–564. [PubMed]
  • Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993 Sep 2;365(6441):61–65. [PubMed]
  • Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992 Dec 18;258(5090):1946–1949. [PubMed]
  • Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995 Jun 29;50(1):83–90. [PubMed]
  • Voth EA, Schwartz RH. Medicinal applications of delta-9-tetrahydrocannabinol and marijuana. Ann Intern Med. 1997 May 15;126(10):791–798. [PubMed]
  • Piomelli D, Giuffrida A, Calignano A, Rodríguez de Fonseca F. The endocannabinoid system as a target for therapeutic drugs. Trends Pharmacol Sci.2000 Jun;21(6):218–224. [PubMed]
  • De Petrocellis L, Melck D, Palmisano A, Bisogno T, Laezza C, Bifulco M, Di Marzo V. The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8375–8380.[PMC free article] [PubMed]
  • Sánchez C, Galve-Roperh I, Canova C, Brachet P, Guzmán M. Delta9-tetrahydrocannabinol induces apoptosis in C6 glioma cells. FEBS Lett. 1998 Sep 25;436(1):6–10. [PubMed]
  • Ruiz L, Miguel A, Díaz-Laviada I. Delta9-tetrahydrocannabinol induces apoptosis in human prostate PC-3 cells via a receptor-independent mechanism. FEBS Lett.1999 Sep 24;458(3):400–404. [PubMed]
  • Maccarrone M, Lorenzon T, Bari M, Melino G, Finazzi-Agro A. Anandamide induces apoptosis in human cells via vanilloid receptors. Evidence for a protective role of cannabinoid receptors. J Biol Chem. 2000 Oct 13;275(41):31938–31945.[PubMed]
  • Galve-Roperh I, Sánchez C, Cortés ML, Gómez del Pulgar T, Izquierdo M, Guzmán M. Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med. 2000 Mar;6(3):313–319. [PubMed]
  • Kolesnick RN, Krönke M. Regulation of ceramide production and apoptosis.Annu Rev Physiol. 1998;60:643–665. [PubMed]
  • Hannun YA, Luberto C. Ceramide in the eukaryotic stress response. Trends Cell Biol. 2000 Feb;10(2):73–80. [PubMed]
  • Huwiler A, Kolter T, Pfeilschifter J, Sandhoff K. Physiology and pathophysiology of sphingolipid metabolism and signaling. Biochim Biophys Acta. 2000 May 31;1485(2-3):63–99. [PubMed]
  • Sánchez C, Rueda D, Ségui B, Galve-Roperh I, Levade T, Guzmán M. The CB(1) cannabinoid receptor of astrocytes is coupled to sphingomyelin hydrolysis through the adaptor protein fan. Mol Pharmacol. 2001 May;59(5):955–959. [PubMed]
  • Guzmán M, Galve-Roperh I, Sánchez C. Ceramide: a new second messenger of cannabinoid action. Trends Pharmacol Sci. 2001 Jan;22(1):19–22. [PubMed]
  • Galve-Roperh I, Sánchez C, Ségui B, Haro A, Díaz-Laviada I, Levade T. Evidence for the lack of involvement of sphingomyelin hydrolysis in the tumor necrosis factor-induced secretion of nerve growth factor in primary astrocyte cultures. J Neurochem. 1998 Aug;71(2):498–505. [PubMed]
  • Sánchez C, Galve-Roperh I, Rueda D, Guzmán M. Involvement of sphingomyelin hydrolysis and the mitogen-activated protein kinase cascade in the Delta9-tetrahydrocannabinol-induced stimulation of glucose metabolism in primary astrocytes. Mol Pharmacol. 1998 Nov;54(5):834–843. [PubMed]
  • Gómez del Pulgar T, Velasco G, Guzmán M. The CB1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt. Biochem J. 2000 Apr 15;347(Pt 2):369–373. [PMC free article] [PubMed]
  • Blázquez C, Geelen MJ, Velasco G, Guzmán M. The AMP-activated protein kinase prevents ceramide synthesis de novo and apoptosis in astrocytes. FEBS Lett. 2001 Feb 2;489(2-3):149–153. [PubMed]
  • Hanada K, Hara T, Nishijima M. Purification of the serine palmitoyltransferase complex responsible for sphingoid base synthesis by using affinity peptide chromatography techniques. J Biol Chem. 2000 Mar 24;275(12):8409–8415.[PubMed]
  • Hanada K, Hara T, Nishijima M, Kuge O, Dickson RC, Nagiec MM. A mammalian homolog of the yeast LCB1 encodes a component of serine palmitoyltransferase, the enzyme catalyzing the first step in sphingolipid synthesis. J Biol Chem. 1997 Dec 19;272(51):32108–32114. [PubMed]
  • Xu J, Yeh CH, Chen S, He L, Sensi SL, Canzoniero LM, Choi DW, Hsu CY. Involvement of de novo ceramide biosynthesis in tumor necrosis factor-alpha/cycloheximide-induced cerebral endothelial cell death. J Biol Chem. 1998 Jun 26;273(26):16521–16526. [PubMed]
  • Brann AB, Scott R, Neuberger Y, Abulafia D, Boldin S, Fainzilber M, Futerman AH. Ceramide signaling downstream of the p75 neurotrophin receptor mediates the effects of nerve growth factor on outgrowth of cultured hippocampal neurons.J Neurosci. 1999 Oct 1;19(19):8199–8206. [PubMed]
  • Levade T, Jaffrézou JP. Signalling sphingomyelinases: which, where, how and why? Biochim Biophys Acta. 1999 Apr 19;1438(1):1–17. [PubMed]
  • Dickson RC, Lester RL, Nagiec MM. Serine palmitoyltransferase. Methods Enzymol. 2000;311:3–9. [PubMed]
  • Schubert KM, Scheid MP, Duronio V. Ceramide inhibits protein kinase B/Akt by promoting dephosphorylation of serine 473. J Biol Chem. 2000 May 5;275(18):13330–13335. [PubMed]
  • Blázquez C, Galve-Roperh I, Guzmán M. De novo-synthesized ceramide signals apoptosis in astrocytes via extracellular signal-regulated kinase. FASEB J. 2000 Nov;14(14):2315–2322. [PubMed]
  • Guzmán M, Sánchez C, Galve-Roperh I. Control of the cell survival/death decision by cannabinoids. J Mol Med (Berl) 2001;78(11):613–625. [PubMed]
  • Lehtonen JY, Horiuchi M, Daviet L, Akishita M, Dzau VJ. Activation of the de novo biosynthesis of sphingolipids mediates angiotensin II type 2 receptor-induced apoptosis. J Biol Chem. 1999 Jun 11;274(24):16901–16906. [PubMed]
  • Herget T, Esdar C, Oehrlein SA, Heinrich M, Schütze S, Maelicke A, van Echten-Deckert G. Production of ceramides causes apoptosis during early neural differentiation in vitro. J Biol Chem. 2000 Sep 29;275(39):30344–30354.[PubMed]
  • Paumen MB, Ishida Y, Muramatsu M, Yamamoto M, Honjo T. Inhibition of carnitine palmitoyltransferase I augments sphingolipid synthesis and palmitate-induced apoptosis. J Biol Chem. 1997 Feb 7;272(6):3324–3329. [PubMed]
  • Shimabukuro M, Zhou YT, Levi M, Unger RH. Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes. Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2498–2502. [PMC free article] [PubMed]
  • Liao WC, Haimovitz-Friedman A, Persaud RS, McLoughlin M, Ehleiter D, Zhang N, Gatei M, Lavin M, Kolesnick R, Fuks Z. Ataxia telangiectasia-mutated gene product inhibits DNA damage-induced apoptosis via ceramide synthase. J Biol Chem. 1999 Jun 18;274(25):17908–17917. [PubMed]
  • Perry DK, Carton J, Shah AK, Meredith F, Uhlinger DJ, Hannun YA. Serine palmitoyltransferase regulates de novo ceramide generation during etoposide-induced apoptosis. J Biol Chem. 2000 Mar 24;275(12):9078–9084. [PubMed]
  • Weiss B, Stoffel W. Human and murine serine-palmitoyl-CoA transferase–cloning, expression and characterization of the key enzyme in sphingolipid synthesis. Eur J Biochem. 1997 Oct 1;249(1):239–247. [PubMed]
  • Hanada K, Hara T, Fukasawa M, Yamaji A, Umeda M, Nishijima M. Mammalian cell mutants resistant to a sphingomyelin-directed cytolysin. Genetic and biochemical evidence for complex formation of the LCB1 protein with the LCB2 protein for serine palmitoyltransferase. J Biol Chem. 1998 Dec 11;273(50):33787–33794. [PubMed]
  • Farrell AM, Uchida Y, Nagiec MM, Harris IR, Dickson RC, Elias PM, Holleran WM. UVB irradiation up-regulates serine palmitoyltransferase in cultured human keratinocytes. J Lipid Res. 1998 Oct;39(10):2031–2038. [PubMed]
  • Yuan J, Yankner BA. Apoptosis in the nervous system. Nature. 2000 Oct 12;407(6805):802–809. [PubMed]
  • Murray B, Alessandrini A, Cole AJ, Yee AG, Furshpan EJ. Inhibition of the p44/42 MAP kinase pathway protects hippocampal neurons in a cell-culture model of seizure activity. Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11975–11980.[PMC free article] [PubMed]
  • Rundén E, Seglen PO, Haug FM, Ottersen OP, Wieloch T, Shamloo M, Laake JH. Regional selective neuronal degeneration after protein phosphatase inhibition in hippocampal slice cultures: evidence for a MAP kinase-dependent mechanism. J Neurosci. 1998 Sep 15;18(18):7296–7305. [PubMed]
  • York RD, Yao H, Dillon T, Ellig CL, Eckert SP, McCleskey EW, Stork PJ. Rap1 mediates sustained MAP kinase activation induced by nerve growth factor.Nature. 1998 Apr 9;392(6676):622–626. [PubMed]
  • Dawkins JL, Hulme DJ, Brahmbhatt SB, Auer-Grumbach M, Nicholson GA. Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. Nat Genet. 2001 Mar;27(3):309–312. [PubMed]
  • Bejaoui K, Wu C, Scheffler MD, Haan G, Ashby P, Wu L, de Jong P, Brown RH., Jr SPTLC1 is mutated in hereditary sensory neuropathy, type 1. Nat Genet. 2001 Mar;27(3):261–262. [PubMed]

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