Involvement of Sphingolipids in Apoptin-Induced Cell Killing

Xiang Liu, Youssef H. 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 journalArticlepeer-review

30 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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