BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Celecoxib-mediated activation of endoplasmic reticulum stress induces de novo ceramide biosynthesis and apoptosis in hepatoma HepG2 cells

  • Maeng, Hyo Jin (Department of Life Science, Gachon University) ;
  • Song, Jae-Hwi (Department of Life Science, Gachon University) ;
  • Kim, Goon-Tae (Department of Life Science, Gachon University) ;
  • Song, Yoo-Jeong (Department of Life Science, Gachon University) ;
  • Lee, Kangpa (Department of Physiology, Konkuk University School of Medicine) ;
  • Kim, Jae-Young (Department of Life Science, Gachon University) ;
  • Park, Tae-Sik (Department of Life Science, Gachon University)
  • Received : 2016.11.30
  • Accepted : 2017.02.06
  • Published : 2017.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

Ceramides are the major sphingolipid metabolites involved in cell survival and apoptosis. When HepG2 hepatoma cells were treated with celecoxib, the expression of the genes in de novo sphingolipid biosynthesis and sphingomyelinase pathway was upregulated and cellular ceramide was elevated. In addition, celecoxib induced endoplasmic reticulum (ER) stress in a time-dependent manner. SPTLC2, a subunit of serine palmitoyltransferase, was overexpressed by adenovirus. Adenoviral overexpression of SPTLC2 (AdSPTLC2) decreased cell viability of HEK293 and HepG2 cells. In addition, AdSPTLC2 induced apoptosis via the caspase-dependent apoptotic pathway and elevated cellular ceramide, sphingoid bases, and dihydroceramide. However, overexpression of SPTLC2 did not induce ER stress. Collectively, celecoxib activates de novo sphingolipid biosynthesis and the combined effects of elevated ceramide and transcriptional activation of ER stress induce apoptosis. However, activation of de novo sphingolipid biosynthesis does not activate ER stress in hepatoma cells and is distinct from the celecoxib-mediated activation of ER stress.

Keywords

References

  1. Kitatani K, Idkowiak-Baldys J and Hannun YA (2008) The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell Signal 20, 1010-1018 https://doi.org/10.1016/j.cellsig.2007.12.006
  2. Menaldino DS, Bushnev A, Sun A et al (2003) Sphingoid bases and de novo ceramide synthesis: enzymes involved, pharmacology and mechanisms of action. Pharmacol Res 47, 373-381 https://doi.org/10.1016/S1043-6618(03)00054-9
  3. Brenner B, Ferlinz K, Grassme H et al (1998) Fas/CD95/Apo-I activates the acidic sphingomyelinase via caspases. Cell Death Differ 5, 29-37 https://doi.org/10.1038/sj.cdd.4400307
  4. Goldkorn T, Balaban N, Shannon M et al (1998) H2O2 acts on cellular membranes to generate ceramide signaling and initiate apoptosis in tracheobronchial epithelial cells. J Cell Sci 111 (Pt 21), 3209-3220
  5. Jenkins GM, Cowart LA, Signorelli P, Pettus BJ, Chalfant CE and Hannun YA (2002) Acute activation of de novo sphingolipid biosynthesis upon heat shock causes an accumulation of ceramide and subsequent dephosphorylation of SR proteins. J Biol Chem 277, 42572-42578 https://doi.org/10.1074/jbc.M207346200
  6. Baran Y, Salas A, Senkal CE et al (2007) Alterations of ceramide/sphingosine 1-phosphate rheostat involved in the regulation of resistance to imatinib-induced apoptosis in K562 human chronic myeloid leukemia cells. J Biol Chem 282, 10922-10934 https://doi.org/10.1074/jbc.M610157200
  7. Wang H, Maurer BJ, Reynolds CP and Cabot MC (2001) N-(4-hydroxyphenyl)retinamide elevates ceramide in neuroblastoma cell lines by coordinate activation of serine palmitoyltransferase and ceramide synthase. Cancer Res 61, 5102-5105
  8. Perry DK, Carton J, Shah AK, Meredith F, Uhlinger DJ and Hannun YA (2000) Serine palmitoyltransferase regulates de novo ceramide generation during etoposide-induced apoptosis. J Biol Chem 275, 9078-9084 https://doi.org/10.1074/jbc.275.12.9078
  9. Grosch S, Tegeder I, Niederberger E, Brautigam L and Geisslinger G (2001) COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib. FASEB J 15, 2742-2744 https://doi.org/10.1096/fj.01-0299fje
  10. Kim HS, Kim T, Kim MK, Suh DH, Chung HH and Song YS (2013) Cyclooxygenase-1 and -2: molecular targets for cervical neoplasia. J Cancer Prev 18, 123-134 https://doi.org/10.15430/JCP.2013.18.2.123
  11. Zhang H, Li Z and Wang K (2014) Combining sorafenib with celecoxib synergistically inhibits tumor growth of non-small cell lung cancer cells in vitro and in vivo. Oncol Rep 31, 1954-1960 https://doi.org/10.3892/or.2014.3026
  12. Schiffmann S, Sandner J, Schmidt R et al (2009) The selective COX-2 inhibitor celecoxib modulates sphingolipid synthesis. J Lipid Res 50, 32-40 https://doi.org/10.1194/jlr.M800122-JLR200
  13. Truman JP, Garcia-Barros M, Obeid LM and Hannun YA (2014) Evolving concepts in cancer therapy through targeting sphingolipid metabolism. Biochim Biophys Acta 1841, 1174-1188 https://doi.org/10.1016/j.bbalip.2013.12.013
  14. Schroder M and Kaufman RJ (2005) ER stress and the unfolded protein response. Mutat Res 569, 29-63 https://doi.org/10.1016/j.mrfmmm.2004.06.056
  15. Puthalakath H, O'Reilly LA, Gunn P et al (2007) ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129, 1337-1349 https://doi.org/10.1016/j.cell.2007.04.027
  16. Kucuksayan E, Konuk EK, Demir N, Mutus B and Aslan M (2014) Neutral sphingomyelinase inhibition decreases ER stress-mediated apoptosis and inducible nitric oxide synthase in retinal pigment epithelial cells. Free Radic Biol Med 72, 113-123 https://doi.org/10.1016/j.freeradbiomed.2014.04.013
  17. Senkal CE, Ponnusamy S, Bielawski J, Hannun YA and Ogretmen B (2010) Antiapoptotic roles of ceramidesynthase-6-generated C16-ceramide via selective regulation of the ATF6/CHOP arm of ER-stress-response pathways. FASEB J 24, 296-308 https://doi.org/10.1096/fj.09-135087
  18. Senkal CE, Ponnusamy S, Manevich Y et al (2011) Alteration of ceramide synthase 6/C16-ceramide induces activating transcription factor 6-mediated endoplasmic reticulum (ER) stress and apoptosis via perturbation of cellular Ca2+ and ER/Golgi membrane network. J Biol Chem 286, 42446-42458 https://doi.org/10.1074/jbc.M111.287383
  19. Hannun YA and Luberto C (2000) Ceramide in the eukaryotic stress response. Trends Cell Biol 10, 73-80 https://doi.org/10.1016/S0962-8924(99)01694-3
  20. Kolesnick R (2002) The therapeutic potential of modulating the ceramide/sphingomyelin pathway. J Clin Invest 110, 3-8 https://doi.org/10.1172/JCI0216127
  21. Hirayama A, Tanahashi N, Daida H et al (2014) Assessing the cardiovascular risk between celecoxib and nonselective nonsteroidal antiinflammatory drugs in patients with rheumatoid arthritis and osteoarthritis. Cir J 78, 194-205
  22. Pereira PA, Trindade BC, Secatto A et al (2013) Celecoxib improves host defense through prostaglandin inhibition during Histoplasma capsulatum infection. Mediators Inflamm 2013, 950981
  23. Tsuji S, Tomita T, Nakase T, Hamada M, Kawai H and Yoshikawa H (2014) Celecoxib, a selective cyclooxygenase-2 inhibitor, reduces level of a bone resorption marker in postmenopausal women with rheumatoid arthritis. Int J Rheum Dis 17, 44-49 https://doi.org/10.1111/1756-185X.12076
  24. Schiffmann S, Sandner J, Schmidt R et al (2009) The selective COX-2 inhibitor celecoxib modulates sphingolipid synthesis. J Lipid Res 50, 32-40 https://doi.org/10.1194/jlr.M800122-JLR200
  25. Hla T and Kolesnick R (2014) C16:0-ceramide signals insulin resistance. Cell Metab 20, 703-705 https://doi.org/10.1016/j.cmet.2014.10.017
  26. Park JW, Park WJ and Futerman AH (2014) Ceramide synthases as potential targets for therapeutic intervention in human diseases. Biochim Biophys Acta 1841, 671-681 https://doi.org/10.1016/j.bbalip.2013.08.019
  27. Liu X, Elojeimy S, Turner LS et al (2008) Acid ceramidase inhibition: a novel target for cancer therapy. Front Biosci 13, 2293-2298 https://doi.org/10.2741/2843
  28. Tamehiro N, Zhou S, Okuhira K et al (2008) SPTLC1 binds ABCA1 to negatively regulate trafficking and cholesterol efflux activity of the transporter. Biochemistry 47, 6138-6147 https://doi.org/10.1021/bi800182t
  29. Tamehiro N, Mujawar Z, Zhou S et al (2009) Cell polarity factor Par3 binds SPTLC1 and modulates monocyte serine palmitoyltransferase activity and chemotaxis. J Biol Chem 284, 24881-24890 https://doi.org/10.1074/jbc.M109.014365
  30. Luo J, Deng ZL, Luo X et al (2007) A protocol for rapid generation of recombinant adenoviruses using the AdEasy system. Nat Protoc 2, 1236-1247 https://doi.org/10.1038/nprot.2007.135
  31. Chen L, Zou X, Zhang RX et al (2016) IGF1 potentiates BMP9-induced osteogenic differentiation in mesenchymal stem cells through the enhancement of BMP/Smad signaling. BMB Rep 49, 122-127 https://doi.org/10.5483/BMBRep.2016.49.2.228
  32. Oh AR, Bae JS, Lee J et al (2016) Ursodeoxycholic acid decreases age-related adiposity and inflammation in mice. BMB Rep 49, 105-110. https://doi.org/10.5483/BMBRep.2016.49.2.173
  33. Lee SY, Hong IK, Kim BR et al (2015) Activation of sphingosine kinase 2 by endoplasmic reticulum stress ameliorates hepatic steatosis and insulin resistance in mice. Hepatology 62, 135-146 https://doi.org/10.1002/hep.27804
  34. Yoo HH, Son J and Kim DH (2006) Liquid chromatography-tandem mass spectrometric determination of ceramides and related lipid species in cellular extracts. J Chromatogr B Analyt Technol Biomed Life Sci 843, 327-333 https://doi.org/10.1016/j.jchromb.2006.06.025