Synergy between all-trans retinoic acid and tumor necrosis factor pathways in acute leukemia cells
| Autor: | Douglas T. Ross, Wilson H. Miller, Leslie Summers deLuca, Caroline Rousseau, Michael Witcher |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Acute promyelocytic leukemia
Transcription Genetic Cellular differentiation medicine.medical_treatment Immunology Retinoic acid Apoptosis Tretinoin Biology Biochemistry chemistry.chemical_compound Tumor Cells Cultured medicine Humans neoplasms Leukemia Gene Expression Regulation Leukemic Tumor Necrosis Factor-alpha organic chemicals NF-kappa B Cell Differentiation Drug Synergism DNA Cell Biology Hematology medicine.disease biological factors Cytokine chemistry Acute Disease Cancer research Tumor necrosis factor alpha Tumor necrosis factor receptor 2 Signal transduction medicine.drug |
| Zdroj: | Blood. 102:237-245 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2002-09-2725 |
| Popis: | The nuclear receptor ligand all-trans retinoic acid (ATRA) causes dramatic terminal differentiation of acute promyelocytic leukemia (APL) cells in vitro and in patients, but it is less active in other malignancies. However, downstream mediators of the effects of ATRA are not well understood. We used a cDNA microarray to search for ATRA-regulated genes in the APL cell line NB4 and found that ATRA regulated several members of the tumor necrosis factor (TNF) pathway. Here we show that TNF can synergize with ATRA to induce differentiation, showing monocytic characteristics more typical of differentiation mediated by TNF than by ATRA. ATRA and TNF can also induce differentiation of the non-APL cell line U937. Underlying this response was an increase in TNF-induced nuclear factor-κB (NF-κB) DNA binding within 2 hours in the presence of ATRA and activation of NF-κB DNA binding and transcriptional activity in response to ATRA alone within 48 hours of ATRA treatment. Furthermore, we found a synergistic induction of the NF-κB target genes BCL-3, Dif-2, and TNF receptor 2 (TNFR2) in response to the combination of TNF and ATRA. These genes have been previously shown to play a role in TNF signaling, and amplification of such genes may represent a mechanism whereby TNF and ATRA can act synergistically. We propose that ATRA can prime cancer cells for differentiation triggered by TNF and suggest that targeting the TNF pathway in combination with ATRA may represent a novel route to treat leukemias. (Blood. 2003;102:237-245) |
| Databáze: | OpenAIRE |
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