Staurosporine sensitizes T lymphoma cells to glucocorticoid-induced apoptosis: role of Nur77 and Bcl-2.

Abstract

Glucocorticoids (GCs) are used for treatment of various hematopoietic malignancies owing to their ability to induce apoptosis. A major obstacle in leukemia therapy is the emergence of GC-resistant cells. Hence, combinatory treatment protocols should be developed that convert GC-resistant leukemia cells into sensitive ones. Here we demonstrate that the broad-acting kinase inhibitor staurosporine (STS) confers GC-sensitivity on GC-resistant T lymphoma cells expressing elevated levels of either Bcl-2 or Bcl-XL, but not on GC-resistant myelogenic leukemia cells expressing Mcl-1 in addition to Bcl-2 and/or Bcl-XL. In T lymphoma cells, STS induces the expression of the pro-apoptotic orphan receptor Nur77 that overcomes the anti-apoptotic effect of Bcl-2, thus enabling GCinduced apoptosis. However, in the myelogenic leukemia cells, STS does not upregulate Nur77. In these cells, the glucocorticoid receptor (GR) is rapidly downregulated by GC and the anti-apoptotic Mcl-1 protein is upregulated by STS, thereby leading to an even more resistant phenotype. Altogether, our data provide a molecular basis for the differential apoptotic response of T lymphoma versus myelogenic leukemia cells to STS and GC. The former being sensitized to GC-induced apoptosis by STS, whereas in the latter, STS intensifies GC resistance. The cell type specific responses should be taken into consideration when combinatory therapy is used for treating hematopoietic malignancies.

• Authors: Shlomit Kfir, Ronit Vogt Sionov, Elazar Zafrir, Yael Zilberman, Eitan Yefenof
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 6 Issue 24 Pg. 3086-96 (Dec 15 2007) ISSN: 1551-4005 [Electronic] United States
• PMID: 18073527 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Glucocorticoids
• Myeloid Cell Leukemia Sequence 1 Protein
• NR4A1 protein, human
• Neoplasm Proteins
• Nuclear Receptor Subfamily 4, Group A, Member 1
• Proto-Oncogene Proteins c-bcl-2
• Receptors, Cytoplasmic and Nuclear
• Receptors, Glucocorticoid
• Receptors, Steroid
• Transcription Factors
• bcl-X Protein
• Phosphotransferases
• Staurosporine

Topics

• Apoptosis (drug effects, physiology)
• Cell Line, Tumor
• Cell Survival (drug effects, physiology)
• DNA-Binding Proteins (physiology)
• Drug Resistance, Neoplasm
• Glucocorticoids (pharmacology, physiology)
• Humans
• Leukemia, Myeloid
• Lymphoma, T-Cell
• Myeloid Cell Leukemia Sequence 1 Protein
• Neoplasm Proteins (metabolism)
• Nuclear Receptor Subfamily 4, Group A, Member 1
• Phosphotransferases (antagonists & inhibitors)
• Proto-Oncogene Proteins c-bcl-2 (metabolism, physiology)
• Receptors, Cytoplasmic and Nuclear (physiology)
• Receptors, Glucocorticoid (metabolism)
• Receptors, Steroid (physiology)
• Staurosporine (pharmacology)
• Transcription Factors (physiology)
• bcl-X Protein (physiology)