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Resistance to APO-1 (CD95) induced apoptosis in T-ALL is determined by a BCL-2 independent anti-apoptotic program
1University Children's Hospital, Heidelberg, Germany.
Abstract:
Selective induction of programmed cell death, apoptosis, may represent a new approach to the treatment of cancer. Apoptosis can be induced by the monoclonal antibody anti-APO-1 directed against the cell surface receptor APO-1, a member of the nerve growth factor (NGF) receptor/tumor necrosis factor (TNF) receptor superfamily. We determined APO-1 expression and sensitivity to anti-APO-1 mediated apoptosis in childhood acute lymphoblastic leukemia cells of T lymphocyte precursor phenotype (T-ALL). APO-1 was constitutively expressed by 21 of 30 T-ALL and by all T-ALL cell lines investigated. However, most APO-1 positive T-ALL were resistant to anti-APO-1 mediated apoptosis. Sensitivity to anti-APO-1 mediated apoptosis was independent of the density of APO-1 expression on the cell surface and independent of the amount of Bcl-2. Incubation of resistant T-ALL with the protein synthesis inhibitor cycloheximide reversed resistance and induced sensitivity to anti-APO-1 mediated apoptosis in most T-ALL. These data suggest that resistance to anti-APO-1 mediated apoptosis in T-ALL is maintained by an active cellular program. Reversion of resistance to sensitivity towards induction of apoptosis in tumors may provide a new basis for successful therapeutic intervention.
Insights
Targeting cancer cell death, apoptosis, shows promise. Researchers found most childhood acute lymphoblastic leukemia (T-ALL) cells express the APO-1 receptor but resist anti-APO-1 antibody treatment, suggesting an active resistance mechanism.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Programmed cell death, or apoptosis, is a potential cancer treatment strategy.
- The APO-1 receptor, part of the NGF/TNF receptor superfamily, mediates apoptosis when targeted by the anti-APO-1 antibody.
- Childhood acute lymphoblastic leukemia (T-ALL) is a significant pediatric cancer.
Purpose of the Study:
- To investigate APO-1 expression and sensitivity to anti-APO-1-induced apoptosis in T-ALL cells.
- To understand the mechanisms underlying resistance to anti-APO-1 therapy in T-ALL.
- To explore potential strategies for overcoming this resistance.
Main Methods:
- Assessing APO-1 receptor expression on T-ALL cells.
- Evaluating the sensitivity of T-ALL cells to anti-APO-1 antibody-mediated apoptosis.
- Analyzing the role of Bcl-2 protein in apoptosis resistance.
- Testing the effect of cycloheximide, a protein synthesis inhibitor, on T-ALL cell apoptosis.
Main Results:
- APO-1 was constitutively expressed in a majority of T-ALL samples (21/30) and cell lines.
- Most APO-1-positive T-ALL cells were resistant to anti-APO-1-induced apoptosis.
- Resistance was not correlated with APO-1 expression levels or Bcl-2 protein amounts.
- Cycloheximide treatment reversed resistance, rendering most T-ALL cells sensitive to anti-APO-1-mediated apoptosis.
Conclusions:
- Resistance to anti-APO-1-induced apoptosis in T-ALL appears to be actively maintained by cellular processes.
- Inhibiting protein synthesis can overcome this resistance, sensitizing T-ALL cells to apoptosis.
- Modulating these resistance mechanisms could offer a novel therapeutic approach for T-ALL treatment.