Abstract
Ceramide is a sphingolipid that acts as a second messenger in ubiquitous, evolutionarily conserved, signaling systems. Emerging data suggest that radiation acts directly on the plasma membrane of several cell types, activating acid sphingomyelinase, which generates ceramide by enzymatic hydrolysis of sphingomyelin. Ceramide then acts as a second messenger in initiating an apoptotic response via the mitochondrial system. Radiation-induced DNA damage can also initiate ceramide generation by activation of mitochondrial ceramide synthase and de novo synthesis of ceramide. In some cells and tissues, BAX is activated downstream of ceramide, regulating commitment to the apoptotic process via release of mitochondrial cytochrome c. Genetic and pharmacologic studies in vivo showed that radiation targets the acid sphingomyelinase apoptotic system of microvascular endothelial cells in the lungs, intestines and brain, as well as in oocytes, to initiate the pathogenesis of tissue damage. Regulated ceramide metabolism may produce metabolites, such as sphingosine 1-phosphate, shown to signal antiapoptosis, thus controlling the intensity of the apoptotic response and constituting a mechanism for radiation sensitivity or resistance. An improved understanding of this signaling system may offer new opportunities for the modulation of radiation effects in the treatment of cancer.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Abraham RT . (2001). Genes. Dev., 15, 2177–2196.
Adam D, Wiegmann K, Adam-Klages S, Ruff A and Kronke M . (1996). J. Biol. Chem., 271, 14617–14622.
Adam-Klages S, Adam D, Wiegmann K, Struve S, Kolanus W, Schneider-Mergener J and Kronke M . (1996). Cell, 86, 937–947.
Allan-Yorke J, Record M, de Preval C, Davrinche C and Davignon JL . (1998). J. Virol., 72, 2316–2322.
Andrieu-Abadie N and Levade T . (2002). Biochim. Biophys. Acta, 1585, 126–134.
Basu S, Bayoumy S, Zhang Y, Lozano J and Kolesnick R . (1998). J. Biol. Chem., 273, 30419–30426.
Bernstein C, Bernstein H, Payne CM and Garewal H . (2002). Mutat. Res., 511, 145–178.
Bohler T, Baumler C, Herr I, Groll A, Kurz M and Debatin KM . (1997). Pediatr. Infect. Dis. J., 16, 754–759.
Bose R, Verheij M, Haimovitz-Friedman A, Scotto K, Fuks Z and Kolesnick R . (1995). Cell, 82, 405–414.
Brenner B, Koppenhoefer U, Weinstock C, Linderkamp O, Lang F and Gulbins E . (1997). J. Biol. Chem., 272, 22173–22181.
Bruno AP, Laurent G, Averbeck D, Demur C, Bonnet J, Bettaieb A, Levade T and Jaffrezou JP . (1998). Cell Death Differ., 5, 172–182.
Chalfant CE, Rathman K, Pinkerman RL, Wood RE, Obeid LM, Ogretmen B and Hannun YA . (2002). J. Biol. Chem., 277, 12587–12595.
Chan TA, Morin PJ, Vogelstein B and Kinzler KW . (1998). Proc. Natl. Acad. Sci. USA, 95, 681–686.
Chmura SJ, Dolan ME, Cha A, Mauceri HJ, Kufe DW and Weichselbaum RR . (2000). Clin. Cancer Res., 6, 737–742.
Chmura SJ, Gupta N, Advani SJ, Kufe DW and Weichselbaum RR . (2001). Semin. Radiat. Oncol., 11, 338–345.
Chmura SJ, Mauceri HJ, Advani S, Heimann R, Beckett MA, Nodzenski E, Quintans J, Kufe DW and Weichselbaum RR . (1997a). Cancer Res., 57, 4340–4347.
Chmura SJ, Nodzenski E, Beckett MA, Kufe DW, Quintans J and Weichselbaum RR . (1997b). Cancer Res., 57, 1270–1275.
Chmura SJ, Nodzenski E, Weichselbaum RR and Quintans J . (1996). Cancer Res., 56, 2711–2714.
Cremesti A, Paris F, Grassme H, Holler N, Tschopp J, Fuks Z, Gulbins E and Kolesnick R . (2001). J. Biol. Chem., 276, 23954–23961.
Cremesti AE, Goni FM and Kolesnick R . (2002). FEBS Lett., 531, 47–53.
Decaudin D, Geley S, Hirsch T, Castedo M, Marchetti P, Macho A, Kofler R and Kroemer G . (1997). Cancer Res., 57, 62–67.
Deiss LP, Galinka H, Berissi H, Cohen O and Kimchi A . (1996). EMBO J., 15, 3861–3870.
Dickson RC, Nagiec EE, Skrzypek M, Tillman P, Wells GB and Lester RL . (1997). J. Biol. Chem., 272, 30196–30200.
Duan RD, Hertervig E, Nyberg L, Hauge T, Sternby B, Lillienau J, Farooqi A and Nilsson A . (1996). Dig. Dis. Sci., 41, 1801–1806.
Fuks Z, Alfieri A, Haimovitz-Friedman A, Seddon A and Cordon-Cardo C . (1995a). Cancer J. Sci. Am., 1, 62.
Fuks Z, Haimovitz-Friedman A and Kolesnick RN . (1995b). Important Adv. Oncol., 19–31.
Gajate C and Mollinedo F . (2001). Blood, 98, 3860–3863.
Garzotto M, Haimovitz-Friedman A, Liao WC, White-Jones M, Huryk R, Heston WD, Cardon-Cardo C, Kolesnick R and Fuks Z . (1999). Cancer Res., 59, 5194–5201.
Garzotto M, White-Jones M, Jiang Y, Ehleiter D, Liao WC, Haimovitz-Friedman A, Fuks Z and Kolesnick R . (1998). Cancer Res., 58, 2260–2264.
Grassme H, Jendrossek V, Bock J, Riehle A and Gulbins E . (2002). J. Immunol., 168, 298–307.
Grassme H, Schwarz H and Gulbins E . (2001). Biochem. Biophys. Res. Commun., 284, 1016–1030.
Gulbins E, Bissonnette R, Mahboubi A, Martin S, Nishioka W, Brunner T, Baier G, Baier-Bitterlich G, Byrd C and Lang F, Koleshick R, Altman A and Green D . (1995). Immunity, 2, 341–351.
Gulbins E and Grassme H . (2002). Biochim. Biophys. Acta, 1585, 139–145.
Gulbins E and Kolesnick R . (2002). Subcell. Biochem., 36, 229–244.
Gulbins E, Szabo I, Baltzer K and Lang F . (1997). Proc. Natl. Acad. Sci. USA, 94, 7661–7666.
Haimovitz-Friedman A, Balaban N, McLoughlin M, Ehleiter D, Michaeli J, Vlodavsky I and Fuks Z . (1994a). Cancer Res., 54, 2591–2597.
Haimovitz-Friedman A, Cordon-Cardo C, Bayoumy S, Garzotto M, McLoughlin M, Gallily R, Edwards III CK, Schuchman EH, Fuks Z and Kolesnick R . (1997). J. Exp. Med., 186, 1831–1841.
Haimovitz-Friedman A, Kan CC, Ehleiter D, Persaud RS, McLoughlin M, Fuks Z and Kolesnick RN . (1994b). J. Exp. Med., 180, 525–535.
Hallahan DE, Virudachalam S, Grdina D and Weichselbaum RR . (1992a). Int. J. Radiat. Oncol. Biol. Phys., 24, 687–692.
Hallahan DE, Virudachalam S, Schwartz JL, Panje N, Mustafi R and Weichselbaum RR . (1992b). Radiat. Res., 129, 345–350.
Hannun YA, Luberto C and Argraves KM . (2001). Biochemistry, 40, 4893–4903.
Horinouchi K, Erlich S, Perl DP, Ferlinz K, Bisgaier CL, Sandhoff K, Desnick RJ, Stewart CL and Schuchman EH . (1995). Nat. Genet., 10, 288–293.
Hueber AO, Bernard AM, Herincs Z, Couzinet A and He HT . (2002). EMBO Rep., 3, 190–196.
Huwiler A, Brunner J, Hummel R, Vervoordeldonk M, Stabel S, van den Bosch H and Pfeilschifter J . (1996). Proc. Natl. Acad. Sci. USA, 93, 6959–6963.
Huwiler A, Johansen B, Skarstad A and Pfeilschifter J . (2001). FASEB J., 15, 7–9.
Jackson SP . (2002). Carcinogenesis, 23, 687–696.
Jaffrezou JP, Bruno AP, Moisand A, Levade T and Laurent G . (2001). FASEB J., 15, 123–133.
Jayadev S, Linardic CM and Hannun YA . (1994). J. Biol. Chem., 269, 5757–5763.
Jenkins GM, Richards A, Wahl T, Mao C, Obeid L and Hannun Y . (1997). J. Biol. Chem., 272, 32566–32572.
Kashiwagi K, Shirai Y, Kuriyama M, Sakai N and Saito N . (2002). J. Biol. Chem., 277, 18037–18045.
Kimura K, Bowen C, Spiegel S and Gelmann EP . (1999). Cancer Res., 59, 1606–1614.
Kolesnick R . (2002). J. Clin. Invest., 110, 3–8.
Kolesnick R and Hannun YA . (1999). Trends Biochem. Sci., 24, 224–225 author reply 227.
Kolesnick RN . (1989). J. Biol. Chem., 264, 7617–7623.
Kolesnick RN . (1991). Prog. Lipid Res., 30, 1–38.
Kolesnick RN and Clegg S . (1988). J. Biol. Chem., 263, 6534–6537.
Kolesnick RN, Goni FM and Alonso A . (2000). J. Cell. Physiol., 184, 285–300.
Kolesnick RN and Paley AE . (1987). J. Biol. Chem., 262, 9204–9210.
Kreder D, Krut O, Adam-Klages S, Wiegmann K, Scherer G, Plitz T, Jensen JM, Proksch E, Steinmann J, Pfeffer K and Kronke M . (1999). EMBO J., 18, 2472–2479.
Lee H, Liao WC, Rimner A, Ehleiter D, Reed JC, Haimovitz-Friedman A, Fuks Z and Kolesnick R . (2003). Submitted for Publication.
Lepple-Wienhues A, Belka C, Laun T, Jekle A, Walter B, Wieland U, Welz M, Heil L, Kun J, Busch G, Weller M, Bamberg M, Gulbins E and Lang F . (1999). Proc. Natl. Acad. Sci. USA, 96, 13795–13800.
Li CM, Park JH, Simonaro CM, He X, Gordon RE, Friedman AH, Ehleiter D, Paris F, Manova K, Hepbildikler S, Fuks Z, Sandhoff K, Kolesnick R, Schuchman EH and Hepbiloikler S . (2002). Genomics, 79, 218–224.
Liao WC, Haimovitz-Friedman A, Persaud RS, McLoughlin M, Ehleiter D, Zhang N, Gatei M, Lavin M, Kolesnick R and Fuks Z . (1999). J. Biol. Chem., 274, 17908–17917.
Lin X, Fuks Z and Kolesnick R . (2000). Crit. Care Med., 28, N87–93.
Liu B, Andrieu-Abadie N, Levade T, Zhang P, Obeid LM and Hannun YA . (1998). J. Biol. Chem., 273, 11313–11320.
Lowe SW, Schmitt EM, Smith SW, Osborne BA and Jacks T . (1993). Nature, 362, 847–849.
Lozano J, Menendez S, Morales A, Ehleiter D, Liao WC, Wagman R, Haimovitz-Friedman A, Fuks Z and Kolesnick R . (2001). J. Biol. Chem., 276, 442–448.
Luberto C, Hassler DF, Signorelli P, Okamoto Y, Sawai H, Boros E, Hazen-Martin DJ, Obeid LM, Hannun YA and Smith GK . (2002). J. Biol. Chem., 277, 41128–41139.
Mandon EC, Ehses I, Rother J, van Echten G and Sandhoff K . (1992). J. Biol. Chem., 267, 11144–11148.
Marathe S, Schissel SL, Yellin MJ, Beatini N, Mintzer R, Williams KJ and Tabas I . (1998). J. Biol. Chem., 273, 4081–4088.
Marchesini NG, Luberto C and Hannun YA . (2003). J. Biol. Chem., 278, 13775–13783.
Martin SJ, Newmeyer DD, Mathias S, Farschon DM, Wang HG, Reed JC, Kolesnick RN and Green DR. . (1995). EMBO J., 14, 5191–5200.
Mathias S, Pena LA and Kolesnick RN . (1998). Biochem. J., 335 (Pt 3), 465–480.
Merrill Jr AH, Schmelz EM, Dillehay DL, Spiegel S, Shayman JA, Schroeder JJ, Riley RT, Voss KA and Wang E . (1997). Toxicol. Appl. Pharmacol., 142, 208–225.
Morita Y, Perez GI, Paris F, Miranda SR, Ehleiter D, Haimovitz-Friedman A, Fuks Z, Xie Z, Reed JC, Schuchman EH, Kolesnick RN and Tilly JL . (2000). Nat. Med., 6, 1109–1114.
Norbury CJ and Hickson ID . (2001). Annu. Rev. Pharmacol. Toxicol., 41, 367–401.
Okazaki T, Bell RM and Hannun YA . (1989). J. Biol. Chem., 264, 19076–19080.
Okazaki T, Bielawska A, Bell RM and Hannun YA . (1990). J. Biol. Chem., 265, 15823–15831.
Paris F, Fuks Z, Kang A, Capodieci P, Juan G, Ehleiter D, Haimovitz-Friedman A, Cordon-Cardo C and Kolesnick R . (2001). Science, 293, 293–297.
Paris F, Perez GI, Fuks Z, Haimovitz-Friedman A, Nguyen H, Bose M, Ilagan A, Hunt PA, Morgan WF, Tilly JL and Kolesnick R . (2002). Nat. Med., 8, 901–902.
Pena LA, Fuks Z and Kolesnick R . (1997). Biochem. Pharmacol., 53, 615–621.
Pena LA, Fuks Z and Kolesnick RN . (2000). Cancer Res., 60, 321–327.
Pettus BJ, Chalfant CE and Hannun YA . (2002). Biochim. Biophys. Acta, 1585, 114–125.
Prinetti A, Chigorno V, Prioni S, Loberto N, Marano N, Tettamanti G and Sonnino S . (2001). J. Biol. Chem., 276, 21136–21145.
Radford IR . (1986). Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med., 49, 611–620.
Rehemtulla A, Hamilton CA, Chinnaiyan AM and Dixit VM . (1997). J. Biol. Chem., 272, 25783–25786.
Rodriguez-Lafrasse C, Alphonse G, Aloy MT, Ardail D, Gerard JP, Louisot P and Rousson R . (2002). Int. J. Cancer, 101, 589–598.
Santana P, Llanes L, Hernandez I, Gallardo G, Quintana J, Gonzalez J, Estevez F, Ruiz de Galarreta C and Fanjul LF . (1995). Endocrinology, 136, 2345–2348.
Santana P, Pena LA, Haimovitz-Friedman A, Martin S, Green D, McLoughlin M, Cordon-Cardo C, Schuchman EH, Fuks Z and Kolesnick R . (1996). Cell, 86, 189–199.
Schissel SL, Jiang X, Tweedie-Hardman J, Jeong T, Camejo EH, Najib J, Rapp JH, Williams KJ and Tabas I . (1998a). J. Biol. Chem., 273, 2738–2746.
Schissel SL, Keesler GA, Schuchman EH, Williams KJ and Tabas I . (1998b). J. Biol. Chem., 273, 18250–18259.
Schissel SL, Schuchman EH, Williams KJ and Tabas I . (1996). J. Biol. Chem., 271, 18431–18436.
Schneider PB and Kennedy EP . (1967). J. Lipid Res., 8, 202–209.
Schuchman EH, Levran O, Pereira LV and Desnick RJ . (1992). Genomics, 12, 197–205.
Schuchman EH, Suchi M, Takahashi T, Sandhoff K and Desnick RJ . (1991). J. Biol. Chem., 266, 8531–8539.
Shimeno H, Soeda S, Yasukouchi M, Okamura N and Nagamatsu A . (1995). Biol. Pharm. Bull., 18, 1335–1339.
Simons K and Ikonen E . (2000). Science, 290, 1721–1726.
Spiegel S, Foster D and Kolesnick R . (1996). Curr. Opin. Cell. Biol., 8, 159–167.
Spiegel S and Kolesnick R . (2002). Leukemia, 16, 1596–1602.
Susin SA, Zamzami N, Castedo M, Hirsch T, Marchetti P, Macho A, Daugas E, Geuskens M and Kroemer G . (1996). J. Exp. Med., 184, 1331–1341.
Tepper AD, de Vries E, van Blitterswijk WJ and Borst J . (1999). J. Clin. Invest., 103, 971–978.
Uckun FM, Schieven GL, Tuel-Ahlgren LM, Dibirdik I, Myers DE, Ledbetter JA and Song CW . (1993). Proc. Natl. Acad. Sci. USA, 90, 252–256.
Verheij M, Bose R, Lin XH, Yao B, Jarvis WD, Grant S, Birrer MJ, Szabo E, Zon LI, Kyriakis JM, Haimovitz-Friedman A, Fuks Z and Kolesnick RN . (1996). Nature, 380, 75–79.
Ward JF . (1988). Prog. Nucleic. Acid Res. Mol. Biol., 35, 95–125.
Wells GB, Dickson RC and Lester RL . (1998). J. Biol. Chem., 273, 7235–7243.
Westwick JK, Bielawska AE, Dbaibo G, Hannun YA and Brenner DA . (1995). J. Biol. Chem., 270, 22689–22692.
Yan F and Polk DB . (2001). Cancer Res., 61, 963–969.
Zhang Y, Yao B, Delikat S, Bayoumy S, Lin XH, Basu S, McGinley M, Chan-Hui PY, Lichenstein H and Kolesnick R . (1997). Cell, 89, 63–72.
Zhou M, Horita DA, Waugh DS, Byrd RA and Morrison DK . (2002). J. Mol. Biol., 315, 435–446.
Zundel W and Giaccia A . (1998). Genes Dev., 12, 1941–1946.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kolesnick, R., Fuks, Z. Radiation and ceramide-induced apoptosis. Oncogene 22, 5897–5906 (2003). https://doi.org/10.1038/sj.onc.1206702
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1206702
Keywords
This article is cited by
-
Ultrasound-stimulated microbubbles enhancement of fractionated radiation for tumor treatment
BMC Cancer (2023)
-
Radiation-induced gastrointestinal (GI) syndrome as a function of age
Cell Death Discovery (2023)
-
MR-guided ultrasound-stimulated microbubble therapy enhances radiation-induced tumor response
Scientific Reports (2023)
-
Phase I study of opaganib, an oral sphingosine kinase 2-specific inhibitor, in relapsed and/or refractory multiple myeloma
Annals of Hematology (2023)
-
Radiotherapy role in non-seminomatous germ cell tumors, radiobiological and technical issues of an unexplored scenario
International Journal of Clinical Oncology (2021)