A caspase-8-independent component in TRAIL/Apo-2L-induced cell death in human rhabdomyosarcoma cells

I. Peták, R. Vernes, K. S. Szucs, M. Anozie, K. Izeradjene, L. Douglas, D. M. Tillman, D. C. Phillips, Janet A. Houghton

Research output: Contribution to journalArticle

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Abstract

Tumor necrosis factor related apoptosis inducing ligand (TRAIL) belongs to the Tumor necrosis factor (TNF) family of death-inducing ligands, and signaling downstream of TRAIL ligation to its receptor(s) remains to be fully elucidated. Components of the death-inducing signaling complex (DISC) and TRAIL signaling downstream of receptor activation were examined in TRAIL - sensitive and -resistant models of human rhabdomyosarcoma (RMS). TRAIL ligation induced DISC formation in TRAIL-sensitive (RD, Rh18, Rh30) and TRAIL-resistant RMS (Rh28, Rh36, Rh41), with recruitment of FADD and procaspase-8. In RD cells, overexpression of dominant-negative FADD (DNFADD) completely abolished TRAIL-induced cell death in contrast to dominant-negative caspase-8 (DNC8), which only partially inhibited TRAIL-induced poptosis, growth inhibition, or loss in clonogenic survival. DNC8 did not inhibit the cleavage of Bid or the activation of Bax. Overexpression of Bcl-2 or Bcl-xL inhibited TRAIL-induced apoptosis, growth inhibition, and loss in clonogenic survival. Bcl-2 and Bcl-xL, but not DNC8, inhibited TRAIL-induced Bax activation. Bcl-xL did not inhibit the early activation of caspase-8 (<4 h) but inhibited cleavage of Bid, suggesting that Bid is cleaved downstream of the mitochondria, independent of caspase-8. Exogenous addition of sphingosine also induced activation of Bax via a caspase-8-and Bid-independent mechanism. Further, inhibition of sphingosine kinase completely protected cells from TRAIL-induced apoptosis. Data demonstrate that in RMS cells, the TRAIL signaling pathway circumvents caspase-8 activation of Bid upstream of the mitochondria and that TRAIL acts at the level of the mitochondria via a mechanism that may involve components of the sphingomyelin cycle.

Original languageEnglish
Pages (from-to)729-739
Number of pages11
JournalCell Death and Differentiation
Volume10
Issue number6
DOIs
Publication statusPublished - Jun 1 2003

Fingerprint

Rhabdomyosarcoma
Caspase 8
Cell Death
Tumor Necrosis Factor-alpha
Apoptosis
Ligands
Death Domain Receptor Signaling Adaptor Proteins
Mitochondria
Ligation
Sphingosine
Survival
Sphingomyelins
Growth

Keywords

  • Apoptosis
  • Bax activation
  • Caspase-8-independent
  • FADD-dependent
  • RMS
  • Sphingosine
  • TRAIL

ASJC Scopus subject areas

  • Cell Biology

Cite this

A caspase-8-independent component in TRAIL/Apo-2L-induced cell death in human rhabdomyosarcoma cells. / Peták, I.; Vernes, R.; Szucs, K. S.; Anozie, M.; Izeradjene, K.; Douglas, L.; Tillman, D. M.; Phillips, D. C.; Houghton, Janet A.

In: Cell Death and Differentiation, Vol. 10, No. 6, 01.06.2003, p. 729-739.

Research output: Contribution to journalArticle

Peták, I, Vernes, R, Szucs, KS, Anozie, M, Izeradjene, K, Douglas, L, Tillman, DM, Phillips, DC & Houghton, JA 2003, 'A caspase-8-independent component in TRAIL/Apo-2L-induced cell death in human rhabdomyosarcoma cells', Cell Death and Differentiation, vol. 10, no. 6, pp. 729-739. https://doi.org/10.1038/sj.cdd.4401232
Peták, I. ; Vernes, R. ; Szucs, K. S. ; Anozie, M. ; Izeradjene, K. ; Douglas, L. ; Tillman, D. M. ; Phillips, D. C. ; Houghton, Janet A. / A caspase-8-independent component in TRAIL/Apo-2L-induced cell death in human rhabdomyosarcoma cells. In: Cell Death and Differentiation. 2003 ; Vol. 10, No. 6. pp. 729-739.
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abstract = "Tumor necrosis factor related apoptosis inducing ligand (TRAIL) belongs to the Tumor necrosis factor (TNF) family of death-inducing ligands, and signaling downstream of TRAIL ligation to its receptor(s) remains to be fully elucidated. Components of the death-inducing signaling complex (DISC) and TRAIL signaling downstream of receptor activation were examined in TRAIL - sensitive and -resistant models of human rhabdomyosarcoma (RMS). TRAIL ligation induced DISC formation in TRAIL-sensitive (RD, Rh18, Rh30) and TRAIL-resistant RMS (Rh28, Rh36, Rh41), with recruitment of FADD and procaspase-8. In RD cells, overexpression of dominant-negative FADD (DNFADD) completely abolished TRAIL-induced cell death in contrast to dominant-negative caspase-8 (DNC8), which only partially inhibited TRAIL-induced poptosis, growth inhibition, or loss in clonogenic survival. DNC8 did not inhibit the cleavage of Bid or the activation of Bax. Overexpression of Bcl-2 or Bcl-xL inhibited TRAIL-induced apoptosis, growth inhibition, and loss in clonogenic survival. Bcl-2 and Bcl-xL, but not DNC8, inhibited TRAIL-induced Bax activation. Bcl-xL did not inhibit the early activation of caspase-8 (<4 h) but inhibited cleavage of Bid, suggesting that Bid is cleaved downstream of the mitochondria, independent of caspase-8. Exogenous addition of sphingosine also induced activation of Bax via a caspase-8-and Bid-independent mechanism. Further, inhibition of sphingosine kinase completely protected cells from TRAIL-induced apoptosis. Data demonstrate that in RMS cells, the TRAIL signaling pathway circumvents caspase-8 activation of Bid upstream of the mitochondria and that TRAIL acts at the level of the mitochondria via a mechanism that may involve components of the sphingomyelin cycle.",
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AU - Anozie, M.

AU - Izeradjene, K.

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