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Intracellular mediators of erucylphosphocholine-induced apoptosis

Abstract

Induction of apoptosis contributes to the cytotoxic action of the intravenously applicable alkylphosphocholine erucylphosphocholine (ErPC). To define molecular requirements for ErPC-induced apoptosis, activation of caspases-8, -9 and -3 and cleavage of the caspase-3 substrates PARP and ICAD were tested in normal Jurkat T cells, Jurkat cells resistant to death receptor (CD95 or TNFα-related apoptosis inducing ligand (TRAIL)-induced apoptosis, Jurkat cells lacking caspase-8 or Fas-associated death domain (FADD) Jurkat cells expressing a dominant-negative caspase-9 or overexpressing Bcl-2 as well as BJAB B-lymphoma cells expressing a dominant-negative FADD (FADD-DN). ErPC induced a time- and dose-dependent apoptotic cell death in Jurkat and BJAB cells, which was characterized by breakdown of the phosphatidylserine asymmetry, depolarization of the mitochondrial membrane potential, release of cytochrome c, activation of caspases-9, -8 and -3, cleavage of PARP and ICAD, as well as chromatin condensation. ErPC-induced apoptosis was independent from CD95-receptor signaling and FADD since CD95- and TRAIL-resistant, caspase-8- and FADD-negative Jurkat cells, as well as BJAB cells expressing FADD-DN were sensitive to ErPC-induced apoptosis. In contrast, inhibition of caspase-9 and overexpression of Bcl-2 significantly reduced ErPC-induced caspase activation and apoptosis. Thus, ErPC triggers apoptosis via a Bcl-2-dependent mitochondrial but death receptor-independent pathway.

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Abbreviations

ALP:

alkyllysophospholipid

APC:

alkylphosphocholine

CCCP:

carbonylcyanide-m-chlorophenylhydrazone

DISC:

death-inducing signaling complex

ErPC:

erucylphosphocholine

FADD:

fas-associated death domain

HePC:

hexadecylphosphocholine

Et-18-OCH3:

1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine

CD95-L::

CD95 ligand

TMRE::

tetramethylrhodamine-ethylester-perchlorate

TRAIL::

TNFα-related apoptosis inducing ligand

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Acknowledgements

The work was supported by a grant from the Federal Ministry of Education and Research (Fö. 01KS9602) and the Interdisciplinary Center of Clinical Research Tübingen (IZKF) to VJ and CB and a grant from the Mildred Scheel Stiftung to (10-1825 Be-II & 10-1970 Be-III) to CB and VJ. We are thankful to P Juo and J Blenis (Boston, MA, USA) for the caspase-8 and FADD-negative Jurkat cells, to V Dixit (Michigan, USA) for the FADD-DN expressing BJAB cells and to E Alnemri (Philadelphia, USA) for the caspase-9-DN construct.

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Correspondence to Verena Jendrossek.

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Jendrossek, V., Müller, I., Eibl, H. et al. Intracellular mediators of erucylphosphocholine-induced apoptosis. Oncogene 22, 2621–2631 (2003). https://doi.org/10.1038/sj.onc.1206355

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Keywords

  • apoptosis
  • erucylphosphocholine
  • caspases
  • mitochondria
  • Bcl-2
  • FADD

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