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Strategies for Tracking Anastasis, A Cell Survival Phenomenon that Reverses Apoptosis

Published on: February 16, 2015

Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of

M A Grotzer1, A Eggert, T J Zuzak

  • 1Division of Oncology, The Children's Hospital of Philadelphia, Pennsylvania 19104, USA.

Oncogene
|October 13, 2000
PubMed

Insights

Childhood primitive neuroectodermal brain tumors (PNETs) can be targeted with TNF-related apoptosis-inducing ligand (TRAIL). TRAIL-resistance in PNETs is linked to a lack of caspase-8, which can be reversed with methyltransferase inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various solid tumors but not normal tissues.
  • Childhood primitive neuroectodermal brain tumors (PNETs) are a significant challenge in pediatric oncology.

Purpose of the Study:

  • To investigate the TRAIL death pathway and its therapeutic potential in human PNET cell lines.
  • To identify mechanisms of TRAIL-resistance in PNETs.

Main Methods:

  • Assessed TRAIL-induced apoptosis in 8 human PNET cell lines.
  • Correlated TRAIL sensitivity with mRNA expression of TRAIL, its receptors (TRAIL-R1-R4), cFLIP, caspase-3, and caspase-8.
  • Investigated the effect of 5-aza-2'-deoxycytidine on TRAIL-resistant PNET cells.

Main Results:

  • Three of 8 PNET cell lines were sensitive to TRAIL-induced apoptosis.
  • TRAIL sensitivity did not correlate with TRAIL receptor or cFLIP expression.
  • TRAIL-sensitive PNETs expressed caspase-8 (mRNA and protein), while resistant PNETs lacked caspase-8 protein.
  • 5-aza-2'-deoxycytidine restored caspase-8 expression and TRAIL sensitivity in resistant PNET cells, suggesting epigenetic regulation.

Conclusions:

  • Loss of caspase-8 mRNA expression is a key mechanism of TRAIL-resistance in PNET cells.
  • Recombinant soluble TRAIL, potentially combined with methyltransferase inhibitors, shows promise for PNET therapy.
  • Epigenetic silencing of caspase-8 may be a targetable vulnerability in PNET treatment.

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