Abstract
The metabolism of glycosphingolipids is strictly regulated during the mitotic cell cycle. Before the G1-to-S transition, the ceramide and glucosylceramide concentration is elevated. Ceramide induces apoptosis synergistically with the pro-apoptotic protein prostate apoptosis response 4 (PAR-4) that may be asymmetrically inherited during cell division. Only one daughter cell dies shortly after mitosis, a mechanism we suggested to regulate the number of neural stem cells during embryonic development. The progeny cells, however, may protect themselves by converting ceramide to glucosylceramide and other glycosphingolipids. In particular, complex gangliosides have been found to sustain cell survival and differentiation. The cell cycle may thus be a turning point for (glyco)sphingolipid metabolism and explain rapid changes of the sphingolipid composition in cells that undergo mitotic cell-fate decisions. In the proposed model termed “Shiva cycle”, progression through the cell cycle, differentiation, or apoptosis may rely on a delicate balance of (glyco)sphingolipid second messengers that modulate the retinoblastoma-dependent G1-to-S transition or caspase-dependent G1-to-apoptosis program. Ceramide-induced cell cycle delay at G0/G1 is either followed by ceramide-induced apoptosis or by conversion of ceramide to glucosylceramide, a proposed key regulatory rheostat that rescues cells from re-entry into a life/death decision at G1-to-S. We propose a mechanistic model for sphingolpid-induced protein scaffolds (“slip”) that regulate cell-fate decisions and will discuss the biological consequences and pharmacological potential of manipulating the (glyco)sphingolipid-dependent cell fate program in cancer and stem cells. Published in 2004.
Similar content being viewed by others
References
London M, London E, J Biol Chem 279, 9997-10004 (2004).
Gulbins E, Kolesnick R, Oncogene 22, 7070-7 (2003).
Kilkus J, Goswami R, Testai FD, Dawson G, J Neurosci Res 72, 65-75 (2003).
van Blitterswijk WJ, van der Luit AH, Veldman RJ, Verheij M, Borst J, Biochem J 369, 199-211 (2003).
Grassme H, Jekle A, Riehle A, Schwarz H, Berger J, Sandhoff K, Kolesnick R, Gulbins E, J Biol Chem 276, 20589-96 (2001).
Grassme H, Cremesti A, Kolesnick R, Gulbins E, Oncogene 22, 5457-70 (2003).
Zhang Y, Yao B, Delikat S, Bayoumy S, Lin XH, Basu S, McGinley M, Chan-Hui PY, Lichenstein H, Kolesnick R, Cell 89, 63-72 (1997).
van Blitterswijk WJ, Biochem J 331 (Pt2), 679-80 (1998).
Mathias S, Dressler KA, Kolesnick RN, Proc Natl Acad Sci USA 88, 10009-13 (1991).
Yao B, Zhang Y, Delikat S, Mathias S, Basu S, Kolesnick R, Nature 378, 307-10 (1995).
Dobrowsky RT, Hannun YA, J Biol Chem 267, 5048-51 (1992).
Hannun YA, Obeid LM, Wolff RA, Adv Lipid Res 25, 43-64 (1993).
Bieberich E, MacKinnon S, Silva J, Noggle S, Condie BG, J Cell Biol 162, 469-79 (2003).
Bieberich E, Hu B, Silva J, MacKinnon S, Yu RK, Fillmore H, Broaddus WC, Ottenbrite RM, Cancer Lett 181, 55-64 (2002).
Bieberich E, MacKinnon S, Silva J, Yu RK, J Biol Chem 276, 44396-404 (2001).
Bieberich E, Kawaguchi T, Yu RK, J Biol Chem 275, 177-81 (2000).
Lozano J, Berra E, Municio MM, Diaz-Meco MT, Dominguez I, Sanz L, Moscat J, J Biol Chem 269, 19200-2 (1994).
Muller G, Ayoub M, Storz P, Rennecke J, Fabbro D, Pfizenmaier K, Embo J 14, 1961-9 (1995).
Huwiler A, Fabbro D, Pfeilschifter J, Biochemistry 37, 14556-62 (1998).
Wang YM, Seibenhener ML, Vandenplas ML, Wooten MW, J Neurosci Res 55, 293-302 (1999).
Kashiwagi K, Shirai Y, Kuriyama M, Sakai N, Saito N, J Biol Chem 277, 18037-45 (2002).
Kajimoto T, Shirai Y, Sakai N, Yamamoto T, Matsuzaki H, Kikkawa U, Saito N, J Biol Chem 279, 12668-76 (2004).
Merrill AH Jr, Biochim Biophys Acta 754, 284-91 (1983).
Merrill AH Jr, J Biol Chem 277, 25843-6 (2002).
Menaldino DS, Bushnev A, Sun A, Liotta DC, Symolon H, Desai K, Dillehay DL, Peng Q, Wang E, Allegood J, Trotman-Pruett S, Sullards MC, Merrill AH Jr, Pharmacol Res 47, 373-81 (2003).
Perry DK, Carton J, Shah AK, Meredith F, Uhlinger DJ, Hannun YA, J Biol Chem 275, 9078-84 (2000).
Herget T, Esdar C, Oehrlein SA, Heinrich M, Schutze S, Maelicke A, van Echten-Deckert G, J Biol Chem 275, 30344-54 (2000).
Blazquez C, Galve-Roperh I, Guzman M, Faseb J 14, 2315-22 (2000).
Perry DK, Biochim Biophys Acta 1585, 146-52 (2002).
Chatterjee S, Sweeley CC, Velicer LF, Biochem Biophys Res Commun 54, 585-92 (1973).
Gahmberg CG, Hakomori S, J Biol Chem 250, 2438-46 (1975).
Yokoyama K, Suzuki M, Kawashima I, Karasawa K, Nojima S, Enomoto T, Tai T, Suzuki A, Setaka M, Eur J Biochem 249, 450-5 (1997).
Jayadev S, Liu B, Bielawska AE, Lee JY, Nazaire F, Pushkareva M, Obeid LM, Hannun YA, J Biol Chem 270, 2047-52 (1995).
Lee JY, Leonhardt LG, Obeid LM, Biochem J 334 (Pt2), 457-61 (1998).
Lee JY, Bielawska AE, Obeid LM, Exp Cell Res 261, 303-11 (2000).
Kim WH, Ghil KC, Lee JH, Yeo SH, Chun YJ, Choi KH, Kim DK, Kim MY, Cancer Lett 151, 39-48 (2000).
Zhu XF, Liu ZC, Xie BF, Feng GK, Zeng YX, Cancer Lett 193, 149-54 (2003).
Kang KH, Kim WH, Choi KH, Exp Cell Res 253, 403-12 (1999).
Kim WH, Kang KH, Kim MY, Choi KH, Biochem Cell Biol 78, 127-35 (2000).
Lopez-Marure R, Ventura JL, Sanchez L, Montano LF, Zentella A, Eur J Biochem 267, 4325-33 (2000).
Alesse E, Zazzeroni F, Angelucci A, Giannini G, Di Marcotullio L, Gulino A, Cell Death Differ 5, 381-9 (1998).
Hanada K, Biochim Biophys Acta 1632, 16-30 (2003).
Yamashita T, Wada R, Sasaki T, Deng C, Bierfreund U, Sandhoff K, Proia RL, Proc Natl Acad Sci USA 96, 9142-7 (1999).
Chalfant CE, Rathman K, Pinkerman RL, Wood RE, Obeid LM, Ogretmen B, Hannun YA, J Biol Chem 277, 12587-95 (2002).
Massiello A, Salas A, Pinkerman RL, Roddy P, Roesser JR, Chalfant CE, J Biol Chem 279, 15799-804 (2004).
Sundararaj KP, Wood RE, Ponnusamy S, Salas AM, Szulc Z, Bielawska A, Obeid LM, Hannun YA, Ogretmen B, J Biol Chem. 279, 6152-62 (2004).
Ogretmen B, Kraveka JM, Schady D, Usta J, Hannun YA, Obeid LM, J Biol Chem 276, 32506-14 (2001).
Cheema SK, Mishra SK, Rangnekar VM, Tari AM, Kumar R, Lopez-Berestein G, J Biol Chem 278, 19995-20005 (2003).
Johnstone RW, See RH, Sells SF, Wang J, Muthukkumar S, Englert C, Haber DA, Licht JD, Sugrue SP, Roberts T, Rangnekar VM, Shi Y, Mol Cell Biol 16, 6945-56 (1996).
Sawada M, Nakashima S, Banno Y, Yamakawa H, Hayashi K, Takenaka K, Nishimura Y, Sakai N, Nozawa Y, Cell Death Differ 7, 761-72 (2000).
Kim SS, Chae HS, Bach JH, Lee MW, Kim KY, Lee WB, Jung YM, Bonventre JV, Suh YH, Oncogene 21, 2020-8 (2002).
Scorrano L, Oakes SA, Opferman JT, Cheng EH, Sorcinelli MD, Pozzan T, Korsmeyer SJ, Science 300, 135-9 (2003).
Wu G, Xie X, Lu ZH, Ledeen RW, Proc Natl Acad Sci USA 98, 307-12 (2001).
Ledeen RW, Wu G, Neurochem Res 27, 637-47 (2002).
Sommer L, Rao M, Prog Neurobiol 66, 1-18 (2002).
Cayouette M, Raff M, Nat Neurosci 5, 1265-9 (2002).
Cai L, Hayes NL, Takahashi T, Caviness VS Jr, Nowakowski RS, J Neurosci Res 69, 731-44 (2002).
Kuida K, Zheng TS, Na S, Kuan C, Yang D, Karasuyama H, Rakic P, Flavell RA, Nature 384, 368-72 (1996).
Hakem R, Hakem A, Duncan GS, Henderson JT, Woo M, Soengas MS, Elia A, de la Pompa JL, Kagi D, Khoo W, Potter J, Yoshida R, Kaufman SA, Lowe SW, Penninger JM, Mak TW, Cell 94, 339-52 (1998).
Yoshida H, Kong YY, Yoshida R, Elia AJ, Hakem A, Hakem R, Penninger JM, Mak TW, Cell 94, 739-50 (1998).
Haydar TF, Kuan CY, Flavell RA, Rakic P, Cereb Cortex 9, 621-6 (1999).
Miller TM, Moulder KL, Knudson CM, Creedon DJ, Deshmukh M, Korsmeyer SJ, Johnson EM Jr, J Cell Biol 139, 205-17 (1997).
Lindsten T, Golden JA, Zong WX, Minarcik J, Harris MH, Thompson CB, J Neurosci 23, 11112-9 (2003).
Schmidt-Kastner PK, Jardine K, Cormier M, McBurney MW, Oncogene 16, 3003-11 (1998).
Savatier P, Huang S, Szekely L, Wiman KG, Samarut J, Oncogene 9, 809-18 (1994).
Savatier P, Afanassieff M, J Soc Biol 196, 117-23 (2002).
Prasad S, Soldatenkov VA, Srinivasarao G, Dritschilo A, Int J Oncol 14, 563-70 (1999).
Yu RK, Prog Brain Res 101, 31-44 (1994).
Liu YY, Han TY, Giuliano AE, Cabot MC, J Biol Chem 274, 1140-6 (1999).
Liu YY, Han TY, Giuliano AE, Cabot MC, Faseb J 15, 719-30 (2001).
Bleicher RJ, Cabot MC, Biochim Biophys Acta 1585, 172-8 (2002).
Marches R, Scheuermann RH, Uhr JW, Cancer Res 58, 691-7 (1998).
Lucero HA, Robbins PW, Arch Biochem Biophys 426, 208-24 (2004).
Munro S, Cell 115, 377-88 (2003).
Lai EC, J Cell Biol 162, 365-70 (2003).
Hoekstra D, Maier O, van der Wouden JM, Slimane TA, van ISC, J Lipid Res 44, 869-77 (2003).
Carter WG, Hakomori S, J Biol Chem 256, 6953-60 (1981).
Yanagisawa K, Odaka A, Suzuki N, Ihara Y, Nat Med 1, 1062-6 (1995).
Ariga T, Yu RK, Ann NY Acad Sci 845, 403 (1998).
Ariga T, Kobayashi K, Hasegawa A, Kiso M, Ishida H, Miyatake T, Arch Biochem Biophys 388, 225-30 (2001).
Kakio A, Nishimoto S, Yanagisawa K, Kozutsumi Y, Matsuzaki K, Biochemistry 41, 7385-90 (2002).
Matsuoka Y, Saito M, LaFrancois J, Gaynor K, Olm V, Wang L, Casey E, Lu Y, Shiratori C, Lemere C, Duff K, J Neurosci 23, 29-33 (2003).
Puglielli L, Ellis BC, Saunders AJ, Kovacs DM, J Biol Chem 278, 19777-83 (2003).
Klein TR, Kirsch D, Kaufmann R, Riesner D, Biol Chem 379, 655-66 (1998).
Naslavsky N, Shmeeda H, Friedlander G, Yanai A, Futerman AH, Barenholz Y, Taraboulos A, J Biol Chem 274, 20763-71 (1999).
Mahfoud R, Garmy N, Maresca M, Yahi N, Puigserver A, Fantini J, J Biol Chem 277, 11292-6 (2002).
Mattei V, Garofalo T, Misasi R, Gizzi C, Mascellino MT, Dolo V, Pontieri GM, Sorice M, Pavan A, Neurochem Res 27, 743-9 (2002).
Hayashi H, Kimura N, Yamaguchi H, Hasegawa K, Yokoseki T, Shibata M, Yamamoto N, Michikawa M, Yoshikawa Y, Terao K, Matsuzaki K, Lemere CA, Selkoe DJ, Naiki H, Yanagisawa K, J Neurosci 24, 4894-902 (2004).
Yamashita T, Hashiramoto A, Haluzik M, Mizukami H, Beck S, Norton A, Kono M, Tsuji S, Daniotti JL, Werth N, Sandhoff R, Sandhoff K, Proia RL, Proc Natl Acad Sci USA 100, 3445-9 (2003).
Allende ML, Proia RL, Curr Opin Struct Biol 12, 587-92 (2002).
Hakomori S, Proc Natl Acad Sci USA 99, 10231-3 (2002).
Meuillet EJ, Kroes R, Yamamoto H, Warner TG, Ferrari J, Mania-Farnell B, George D, Rebbaa A, Moskal JR, Bremer EG, Cancer Res 59, 234-40 (1999).
Yates AJ, Rampersaud A, Ann NY Acad Sci 845, 57-71 (1998).
Higashi H, Chen NH, Glycoconj J 20, 49-58 (2004)
Bieberich E, MacKinnon S, Silva J, Li DD, Tencomnao T, Irwin L, Kapitonov D, Yu RK, Biochemistry 41, 11479-87 (2002).
Yu RK, Bieberich E, Xia T, Zeng G, J Lipid Res 45, 783-93 (2004).
Giraudo CG, Maccioni HJ, J Biol Chem 278, 40262-71 (2003).
Doherty P, Ashton SV, Skaper SD, Leon A, Walsh FS, J Cell Biol 117, 1093-9 (1992).
Bieberich E, Kapitonov D, Tencomnao T, Yu RK, Anal Biochem 287, 294-8 (2000).
Andreu JM, Ann NY Acad Sci 466, 626-30 (1986).
Kocha T, Fukuda T, Isobe T, Okuyama T, Chem Pharm Bull (Tokyo) 34, 3791-802 (1986).
Gilbert JM, Strocchi P, Ann NY Acad Sci 466, 89-102 (1986).
Elsen L, Betz R, Schwarzmann G, Sandhoff K, van Echten-Deckert G, Neurochem Res 27, 717-27 (2002).
Alessenko A, Chatterjee S, Mol Cell Biochem 143, 169-74 (1995).
Albi E, Magni MP, Biochem Biophys Res Commun 236, 29-33 (1997).
Herrmann H, Aebi U, Curr Opin Cell Biol 12, 79-90 (2000).
Chen N, Furuya S, Shinoda Y, Yumoto M, Ohtake A, Sato K, Doi H, Hashimoto Y, Kudo Y, Higashi H, Neuroscience 122, 985-95 (2003).
Palestini P, Pitto M, Tedeschi G, Ferraretto A, Parenti M, Brunner J, Masserini M, J Biol Chem 275, 9978-85 (2000).
Roussigne M, Cayrol C, Clouaire T, Amalric F, Girard JP, Oncogene 22, 2432-42 (2003).
Guo A, Salomoni P, Luo J, Shih A, Zhong S, Gu, Paolo Pandolfi P, Nat Cell Biol 2, 730-6 (2000).
Charles AG, Han TY, Liu YY, Hansen N, Giuliano AE, Cabot MC, Cancer Chemother Pharmacol 47, 444-50 (2001).
Ferraro C, Quemeneur L, Fournel S, Prigent AF, Revillard JP, Bonnefoy-Berard N, Cell Death Differ 7, 197-206 (2000).
Inokuchi J, Mason I, Radin NS, Cancer Lett 38, 23-30 (1987).
Sietsma H, Veldman RJ, Kolk D, Ausema B, Nijhof W, Kamps W, Vellenga E, Kok JW, Clin Cancer Res 6, 942-8 (2000).
Bieberich E, Freischutz B, Suzuki M, Yu RK, J Neurochem 72, 1040-9 (1999).
Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH, Nat Med 10, 55-63 (2004).
Barber AJ, Nakamura M, Wolpert EB, Reiter CE, Seigel GM, Antonetti DA, Gardner TW, J Biol Chem 276, 32814-21 (2001).
Rusnati M, Urbinati C, Tanghetti E, Dell'Era P, Lortat-Jacob H, Presta M, Proc Natl Acad Sci USA 99, 4367-72 (2002).
Augustinsson LE, Blennow K, Blomstrand C, Brane G, Ekman R, Fredman P, Karlsson I, Kihlgren M, Lehmann W, Lekman A, Mansson JE, Ramstrom I, Wallin A, Wikkelso C, Gottfries CG, Svennerholm L, Dement Geriatr Cogn Disord 8, 26-33 (1997).
Svennerholm L, Life Sci 55, 2125-34 (1994).
Zhang H, Wang JZ, Sun HY, Zhang JN, Yang SY, Chin J Traumatol 7, 3-6 (2004).
Suetake K, Liour SS, Tencomnao T, Yu RK, J Neurosci Res 74, 769-76 (2003).
Liour SS, Kapitonov D, Yu RK, J Neurosci Res 62, 363-73 (2000).
Takamiya K, Yamamoto A, Furukawa K, Yamashiro S, Shin M, Okada M, Fukumoto S, Haraguchi M, Takeda N, Fujimura K, Sakae M, Kishikawa M, Shiku H, Aizawa S, Proc Natl Acad Sci USA 93, 10662-7 (1996).
Ishibashi T, Dupree JL, Ikenaka K, Hirahara Y, Honke K, Peles E, Popko B, Suzuki K, Nishino H, Baba H, J Neurosci 22, 6507-14 (2002).
Kopper L, Hajdu M, Pathol Oncol Res 10, 69-73 (2004).
Mora J, Cheung NK, Juan G, Illei P, Cheung I, Akram M, Chi S, Ladanyi M, Cordon-Cardo C, Gerald WL, Cancer Res 61, 6892-8 (2001).
Ishikawa S, Acta Pathol Jpn 27, 697-711 (1977).
Brickman JM, Burdon TG, Nat Genet 32, 557-8 (2002).
Setoguchi T, Taga T, Kondo T, Cell Cycle 3, 414-5 (2004).
Kondo T, Setoguchi T, Taga T, Proc Natl Acad Sci USA 101, 781-6 (2004).
Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB, Cancer Res 63, 5821-8 (2003).
Kannagi R, Cochran NA, Ishigami F, Hakomori S, Andrews PW, Knowles BB, Solter D, Embo J 2, 2355-61 (1983).
Damjanov I, Fox N, Knowles BB, Solter D, Lange PH, Fraley EE, Am J Pathol 108, 225-30 (1982).
Kannagi R, Levery SB, Ishigami F, Hakomori S, Shevinsky LH, Knowles BB, Solter D, J Biol Chem 258, 8934-42 (1983).
Ariga T, Yu RK, Neurochem Res 23, 291-303 (1998).
Ariga T, Bhat S, Kanda T, Yamawaki M, Tai T, Kushi Y, Kasama T, Handa S, Yu RK, Glycoconj J 13, 135-45 (1996).
Hakomori S, Adv Exp Med Biol 491, 369-402 (2001).
Fenderson BA, Andrews PW, Nudelman E, Clausen H, Hakomori S, Dev Biol 122, 21-34 (1987).
Houghton AN, Mintzer D, Cordon-Cardo C, Welt S, Fliegel B, Vadhan S, Carswell E, Melamed MR, Oettgen HF, Old LJ, Proc Natl Acad Sci USA 82, 1242-6 (1985).
Cheung NK, Lazarus H, Miraldi FD, Abramowsky CR, Kallick S, Saarinen UM, Spitzer T, Strandjord SE, Coccia PF, Berger NA, J Clin Oncol 5, 1430-40 (1987).
Krug LM, Semin Oncol 31, 112-6 (2004).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bieberich, E. Integration of glycosphingolipid metabolism and cell-fate decisions in cancer and stem cells: Review and Hypothesis. Glycoconj J 21, 315–327 (2004). https://doi.org/10.1023/B:GLYC.0000046274.35732.47
Issue Date:
DOI: https://doi.org/10.1023/B:GLYC.0000046274.35732.47