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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Links between accelerated replicative cellular senescence and down-regulation of SPHK1 transcription

  • Kim, Min Kyung (Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Lee, Wooseong (Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Yoon, Gang-Ho (Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Chang, Eun-Ju (Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Choi, Sun-Cheol (Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kim, Seong Who (Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine)
  • Received : 2019.01.07
  • Accepted : 2019.01.28
  • Published : 2019.03.31
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Abstract

We have identified a mechanism to diminish the proliferative capacity of cells during cell expansion using human adipose-derived stromal cells (hAD-SCs) as a model of replicative senescence. hAD-SCs of high-passage numbers exhibited a reduced proliferative capacity with accelerated cellular senescence. Levels of key bioactive sphingolipids were significantly increased in these senescent hAD-SCs. Notably, the transcription of sphingosine kinase 1 (SPHK1) was down-regulated in hAD-SCs at high-passage numbers. SPHK1 knockdown as well as inhibition of its enzymatic activity impeded the proliferation of hAD-SCs, with concomitant induction of cellular senescence and accumulation of sphingolipids, as seen in high-passage cells. SPHK1 knockdown-accelerated cellular senescence was attenuated by co-treatment with sphingosine-1-phosphate and an inhibitor of ceramide synthesis, fumonisin $B_1$, but not by treatment with either one alone. Together, these results suggest that transcriptional down-regulation of SPHK1 is a critical inducer of altered sphingolipid profiles and enhances replicative senescence during multiple rounds of cell division.

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References

  1. Goni FM and Alonso A (2006) Biophysics of sphingolipids I. Membrane properties of sphingosine, ceramides and other simple sphingolipids. Biochim Biophys Acta 1758, 1902-1921 https://doi.org/10.1016/j.bbamem.2006.09.011
  2. Hannun YA and Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9, 139-150 https://doi.org/10.1038/nrm2329
  3. Adada M, Luberto C and Canals D (2016) Inhibitors of the sphingomyelin cycle: Sphingomyelin synthases and sphingomyelinases. Chem Phys Lipids 197, 45-59 https://doi.org/10.1016/j.chemphyslip.2015.07.008
  4. Hernandez-Corbacho MJ, Salama MF, Canals D, Senkal CE and Obeid LM (2017) Sphingolipids in mitochondria. Biochim Biophys Acta Mol Cell Biol Lipids 1862, 56-68 https://doi.org/10.1016/j.bbalip.2016.09.019
  5. Venable ME, Lee JY, Smyth MJ, Bielawska A and Obeid LM (1995) Role of ceramide in cellular senescence. J Biol Chem 270, 30701-30708 https://doi.org/10.1074/jbc.270.51.30701
  6. Kolesnick RN, Goni FM and Alonso A (2000) Compartmentalization of ceramide signaling: physical foundations and biological effects. J Cell Physiol 184, 285-300 https://doi.org/10.1002/1097-4652(200009)184:3<285::AID-JCP2>3.0.CO;2-3
  7. Zhang H, Desai NN, Olivera A, Seki T, Brooker G and Spiegel S (1991) Sphingosine-1-phosphate, a novel lipid, involved in cellular proliferation. J Cell Biol 114, 155-167 https://doi.org/10.1083/jcb.114.1.155
  8. Trayssac M, Hannun YA and Obeid LM (2018) Role of sphingolipids in senescence: implication in aging and age-related diseases. J Clin Invest 128, 2702-2712 https://doi.org/10.1172/JCI97949
  9. Campisi J (1997) The biology of replicative senescence. Eur J Cancer 33, 703-709 https://doi.org/10.1016/S0959-8049(96)00058-5
  10. Hayflick L and Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25, 585-621 https://doi.org/10.1016/0014-4827(61)90192-6
  11. Flatt T (2012) A new definition of aging? Front Genet 3, 148 https://doi.org/10.3389/fgene.2012.00148
  12. Sherr CJ and DePinho RA (2000) Cellular senescence: mitotic clock or culture shock? Cell 102, 407-410 https://doi.org/10.1016/S0092-8674(00)00046-5
  13. Michaloglou C, Vredeveld LC, Soengas MS et al (2005) BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720-724 https://doi.org/10.1038/nature03890
  14. Chen QM, Prowse KR, Tu VC, Purdom S and Linskens MH (2001) Uncoupling the senescent phenotype from telomere shortening in hydrogen peroxide-treated fibroblasts. Exp Cell Res 265, 294-303 https://doi.org/10.1006/excr.2001.5182
  15. Lowe SW, Cepero E and Evan G (2004) Intrinsic tumour suppression. Nature 432, 307-315 https://doi.org/10.1038/nature03098
  16. Serrano M, Lin AW, McCurrach ME, Beach D and Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593-602 https://doi.org/10.1016/S0092-8674(00)81902-9
  17. Stein GH, Beeson M and Gordon L (1990) Failure to phosphorylate the retinoblastoma gene product in senescent human fibroblasts. Science 249, 666-669 https://doi.org/10.1126/science.2166342
  18. Wei W, Hemmer RM and Sedivy JM (2001) Role of p14(ARF) in replicative and induced senescence of human fibroblasts. Mol Cell Biol 21, 6748-6757 https://doi.org/10.1128/MCB.21.20.6748-6757.2001
  19. Vadas M, Xia P, McCaughan G and Gamble J (2008) The role of sphingosine kinase 1 in cancer: oncogene or non-oncogene addiction? Biochim Biophys Acta 1781, 442-447 https://doi.org/10.1016/j.bbalip.2008.06.007
  20. Meng H, Yuan Y and Lee VM (2011) Loss of sphingosine kinase 1/S1P signaling impairs cell growth and survival of neurons and progenitor cells in the developing sensory ganglia. PLoS One 6, e27150 https://doi.org/10.1371/journal.pone.0027150
  21. Spiegel S and Milstien S (2003) Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol 4, 397-407 https://doi.org/10.1038/nrm1103
  22. Taha TA, Kitatani K, El-Alwani M, Bielawski J, Hannun YA and Obeid LM (2006) Loss of sphingosine kinase-1 activates the intrinsic pathway of programmed cell death: modulation of sphingolipid levels and the induction of apoptosis. FASEB J 20, 482-484 https://doi.org/10.1096/fj.05-4412fje
  23. Bartke N and Hannun YA (2009) Bioactive sphingolipids: metabolism and function. J Lipid Res 50 Suppl, S91-96 https://doi.org/10.1194/jlr.R800080-JLR200
  24. Johnson KR, Johnson KY, Crellin HG et al (2005) Immunohistochemical distribution of sphingosine kinase 1 in normal and tumor lung tissue. J Histochem Cytochem 53, 1159-1166 https://doi.org/10.1369/jhc.4A6606.2005
  25. Xia P, Gamble JR, Wang L et al (2000) An oncogenic role of sphingosine kinase. Curr Biol 10, 1527-1530 https://doi.org/10.1016/S0960-9822(00)00834-4
  26. Olivera A, Kohama T, Edsall L et al (1999) Sphingosine kinase expression increases intracellular sphingosine-1-phosphate and promotes cell growth and survival. J Cell Biol 147, 545-558 https://doi.org/10.1083/jcb.147.3.545
  27. Le Stunff H, Galve-Roperh I, Peterson C, Milstien S and Spiegel S (2002) Sphingosine-1-phosphate phosphohydrolase in regulation of sphingolipid metabolism and apoptosis. J Cell Biol 158, 1039-1049 https://doi.org/10.1083/jcb.200203123
  28. Heffernan-Stroud LA, Helke KL, Jenkins RW, De Costa AM, Hannun YA and Obeid LM (2012) Defining a role for sphingosine kinase 1 in p53-dependent tumors. Oncogene 31, 1166-1175 https://doi.org/10.1038/onc.2011.302
  29. Taha TA, Osta W, Kozhaya L et al (2004) Downregulation of sphingosine kinase-1 by DNA damage: dependence on proteases and p53. J Biol Chem 279, 20546-20554 https://doi.org/10.1074/jbc.M401259200
  30. He Q, Suzuki H, Sharma N and Sharma RP (2006) Ceramide synthase inhibition by fumonisin B1 treatment activates sphingolipid-metabolizing systems in mouse liver. Toxicol Sci 94, 388-397 https://doi.org/10.1093/toxsci/kfl102