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Potential mechanisms of leukemia cell resistance to TRAIL-induced apopotosis

X-S Hao1, J-H Hao, F-T Liu

  • 1Tianjin Cancer Hospital and Cancer Institute, Tianjin, P. R. China.

Apoptosis : an International Journal on Programmed Cell Death
|January 24, 2004
PubMed

Insights

Leukemic cells resist Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis primarily due to low constitutive caspase-8 expression. This deficiency impacts apoptosis signaling, and resistance can develop in both sensitive and resistant cells.

Area of Science:

  • Cancer Biology
  • Apoptosis Research
  • Molecular Oncology

Background:

  • Resistance to Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis is a significant challenge in cancer therapy.
  • The mechanisms underlying TRAIL resistance, whether constitutive or acquired, require further elucidation.

Purpose of the Study:

  • To investigate the mechanisms of TRAIL resistance at various levels of the apoptotic pathway in leukemic cell lines.
  • To compare TRAIL sensitivity and resistance mechanisms between T-lymphoblastic leukemic CEM and chronic myeloid leukemic K562 cells.

Main Methods:

  • Comparative analysis of TRAIL-induced apoptosis in CEM and K562 cell lines.
  • Assessment of key apoptotic pathway components including caspase-8, caspase-3, mitochondrial membrane potential (ΔΨm), NF-κB, Bcl-2 family proteins, and Inhibitors of Apoptosis Proteins (IAPs).

Main Results:

  • CEM cells exhibited greater TRAIL resistance than K562 cells, linked to lower constitutive caspase-8 expression.
  • CEM cells showed impaired TRAIL-induced caspase-3 activation and mitochondrial membrane potential reduction.
  • TRAIL treatment led to upregulation of Bcl-2/Bcl-XL and IAPs (XIAP, cIAP-1, cIAP-2, Survivin), and downregulation of Bax, in both cell lines.
  • CEM cells displayed faster TRAIL-induced NF-κB activation compared to K562 cells.

Conclusions:

  • Deficiency in constitutive caspase-8 expression is a likely contributor to TRAIL resistance in leukemic cells.
  • Leukemic cells, regardless of initial TRAIL sensitivity, can develop resistance to TRAIL-induced apoptosis.
  • Understanding these resistance mechanisms is crucial for developing effective TRAIL-based cancer therapies.

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