Involvement of Sphingolipids in Apoptin-Induced Cell Killing

Xiang Liu, Youssef Zeidan, Saeed Elojeimy, David H. Holman, Ahmed M. El-Zawahry, Gui wen Guo, Alicja Bielawska, Jacek Bielawski, Zdzislaw Szulc, Semyon Rubinchik, Jian Yun Dong, Thomas E. Keane, Mahvash Tavassoli, Yusuf A. Hannun, James S. Norris

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The potential anti-tumor agent Apoptin activates apoptosis in many human cancers and transformed cell lines, but is believed to be less potent in primary cells. Although caspase 3 is activated during apoptin-induced apoptosis, the mechanism of tumor cell killing remains elusive. We now show that apoptin-mediated cell death involves modulation of the sphingomyelin-ceramide pathway. Treating cells with Ad-GFPApoptin resulted in increased ceramide accumulation and enhanced expression of acid sphingomyelinase (ASMase) with a concomitant increase in ASMase activity and decreased sphingomyelin. Using confocal microscopy, ASMase, normally present in the endosomal/lysosomal compartment, was observed to translocate to the cell's periphery. Cotreatment of Ad-GFPApoptin-infected cells with the ASMase inhibitor desipramine (2.5 μM) attenuated (30%; P < 0.01) apoptin-induced cell death. Apoptin was also able to induce a significant decline in sphingosine content by inhibition of ceramide deacylation through down-regulation of acid ceramidase at the protein level. Supporting the role of ceramide in apoptin action, treatment of cells with the combination of an exogenous cell-permeable ceramide analog (C6-ceramide) and Ad-GFPApoptin infection yielded a significant increase (P < 0.01) in apoptosis over either treatment modality alone. Together, these data suggest that apoptin modulates ceramide/sphingolipid metabolism as part of its mechanism of action.

Original languageEnglish (US)
Pages (from-to)627-636
Number of pages10
JournalMolecular Therapy
Volume14
Issue number5
DOIs
StatePublished - Nov 2006
Externally publishedYes

Fingerprint

Sphingolipids
Ceramides
Sphingomyelin Phosphodiesterase
Acids
Sphingomyelins
Apoptosis
Acid Ceramidase
Cell Death
Neoplasms
Transformed Cell Line
Desipramine
Sphingosine
Confocal Microscopy
Caspase 3
Down-Regulation
Infection

Keywords

  • acid ceramidase
  • acid sphingomyelinase
  • apoptin
  • apoptosis
  • ceramide
  • signal transduction
  • sphingolipids

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Liu, X., Zeidan, Y., Elojeimy, S., Holman, D. H., El-Zawahry, A. M., Guo, G. W., ... Norris, J. S. (2006). Involvement of Sphingolipids in Apoptin-Induced Cell Killing. Molecular Therapy, 14(5), 627-636. https://doi.org/10.1016/j.ymthe.2006.07.001

Involvement of Sphingolipids in Apoptin-Induced Cell Killing. / Liu, Xiang; Zeidan, Youssef; Elojeimy, Saeed; Holman, David H.; El-Zawahry, Ahmed M.; Guo, Gui wen; Bielawska, Alicja; Bielawski, Jacek; Szulc, Zdzislaw; Rubinchik, Semyon; Dong, Jian Yun; Keane, Thomas E.; Tavassoli, Mahvash; Hannun, Yusuf A.; Norris, James S.

In: Molecular Therapy, Vol. 14, No. 5, 11.2006, p. 627-636.

Research output: Contribution to journalArticle

Liu, X, Zeidan, Y, Elojeimy, S, Holman, DH, El-Zawahry, AM, Guo, GW, Bielawska, A, Bielawski, J, Szulc, Z, Rubinchik, S, Dong, JY, Keane, TE, Tavassoli, M, Hannun, YA & Norris, JS 2006, 'Involvement of Sphingolipids in Apoptin-Induced Cell Killing', Molecular Therapy, vol. 14, no. 5, pp. 627-636. https://doi.org/10.1016/j.ymthe.2006.07.001
Liu X, Zeidan Y, Elojeimy S, Holman DH, El-Zawahry AM, Guo GW et al. Involvement of Sphingolipids in Apoptin-Induced Cell Killing. Molecular Therapy. 2006 Nov;14(5):627-636. https://doi.org/10.1016/j.ymthe.2006.07.001
Liu, Xiang ; Zeidan, Youssef ; Elojeimy, Saeed ; Holman, David H. ; El-Zawahry, Ahmed M. ; Guo, Gui wen ; Bielawska, Alicja ; Bielawski, Jacek ; Szulc, Zdzislaw ; Rubinchik, Semyon ; Dong, Jian Yun ; Keane, Thomas E. ; Tavassoli, Mahvash ; Hannun, Yusuf A. ; Norris, James S. / Involvement of Sphingolipids in Apoptin-Induced Cell Killing. In: Molecular Therapy. 2006 ; Vol. 14, No. 5. pp. 627-636.
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abstract = "The potential anti-tumor agent Apoptin activates apoptosis in many human cancers and transformed cell lines, but is believed to be less potent in primary cells. Although caspase 3 is activated during apoptin-induced apoptosis, the mechanism of tumor cell killing remains elusive. We now show that apoptin-mediated cell death involves modulation of the sphingomyelin-ceramide pathway. Treating cells with Ad-GFPApoptin resulted in increased ceramide accumulation and enhanced expression of acid sphingomyelinase (ASMase) with a concomitant increase in ASMase activity and decreased sphingomyelin. Using confocal microscopy, ASMase, normally present in the endosomal/lysosomal compartment, was observed to translocate to the cell's periphery. Cotreatment of Ad-GFPApoptin-infected cells with the ASMase inhibitor desipramine (2.5 μM) attenuated (30{\%}; P < 0.01) apoptin-induced cell death. Apoptin was also able to induce a significant decline in sphingosine content by inhibition of ceramide deacylation through down-regulation of acid ceramidase at the protein level. Supporting the role of ceramide in apoptin action, treatment of cells with the combination of an exogenous cell-permeable ceramide analog (C6-ceramide) and Ad-GFPApoptin infection yielded a significant increase (P < 0.01) in apoptosis over either treatment modality alone. Together, these data suggest that apoptin modulates ceramide/sphingolipid metabolism as part of its mechanism of action.",
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AU - Szulc, Zdzislaw

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