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LY303511 amplifies TRAIL-induced apoptosis in tumor cells by enhancing DR5 oligomerization, DISC assembly, and

T W Poh1, S Huang, J L Hirpara

  • 1Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive, Singapore 117597, Singapore.

Cell Death and Differentiation
|June 23, 2007
PubMed

Insights

The small molecule LY303511 enhances tumor cell sensitivity to TRAIL-induced apoptosis by downregulating cFLIP(S) and promoting DR5 oligomerization, offering potential for treating TRAIL-resistant cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Tumor cells with DR4/DR5 receptors are sensitive to TRAIL, but resistance is a clinical challenge.
  • Identifying compounds to restore TRAIL sensitivity is crucial for cancer therapy.
  • Previous studies showed LY294002 and LY303511 sensitized cells to vincristine-induced apoptosis.

Purpose of the Study:

  • To investigate the effect of LY303511 on TRAIL-induced apoptosis in HeLa cells.
  • To elucidate the molecular mechanisms by which LY303511 enhances TRAIL sensitivity.

Main Methods:

  • HeLa cells were preincubated with LY303511 before TRAIL exposure.
  • Assessed apoptosis markers: DNA fragmentation, caspase activation (caspases 2, 3, 8, 9), mitochondrial membrane permeabilization, cytochrome c release, XIAP cleavage, and colony formation.
  • Investigated downstream signaling: cFLIP(S) downregulation, DR5 oligomerization, caspase 8 activation, and Bid cleavage.

Main Results:

  • LY303511 significantly amplified TRAIL-induced apoptosis, evidenced by increased DNA fragmentation and caspase activation.
  • Enhanced TRAIL sensitivity involved mitochondrial pathway activation, including cytochrome c release and caspase 9 activation.
  • LY303511 downregulated cFLIP(S), promoted DR5 oligomerization, and facilitated death-initiating signaling complex formation, leading to caspase 8 activation and Bid cleavage.

Conclusions:

  • LY303511 potentiates TRAIL-induced apoptosis through novel mechanisms involving cFLIP(S) downregulation and DR5 oligomerization.
  • This small molecule shows potential for overcoming TRAIL resistance in tumors.
  • The findings provide a new therapeutic strategy for TRAIL-resistant cancers.

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