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Series GSE28185 Query DataSets for GSE28185
Status Public on Mar 26, 2011
Title The non-steroidal anti-inflammatory drugs Sulindac sulfide and Diclofenac induce apoptosis and differentiation in human acute myeloid leukemia cells through an AP-1 dependent pathway
Organism Homo sapiens
Experiment type Expression profiling by array
Summary Acute myeloid leukemia is a heterogeneous disease with regard to the underlying genetic and molecular pathophysiology. Non-steroidal anti-inflammatory drugs (NSAIDs) exert significant anti-proliferative effects in various malignant cells in vitro and in vivo. Hence, these agents can be utilized to study potential disease specific anti-proliferative pathways. In this study, a total number of 42 bone marrow derived CD34+ cells from de novo AML patients and the AML cell lines THP-1 and HL-60 were treated with the NSAIDs Sulindac sulfide and Diclofenac. We examined viability, apoptosis, differentiation and addressed the molecular mechanisms involved. We found a consistent induction of apoptosis and to some extent myeloid differentiation in NSAID treated AML cells. Comprehensive protein and gene expression profiling of Diclofenac treated AML cells revealed transcriptional activation of GADD45α and its downstream MAPK/JNK pathway as well as increased protein levels of the Caspase-3 precursor. This points towards a role of the c-Jun NH2-terminal kinase (JNK) in NSAID mediated apoptosis. This was dependent on JNK activity as addition of a specific JNK-inhibitor abrogated apoptosis. Furthermore, the AP-1 transcription factor family members’ c-Jun, JunB and Fra-2 were transcriptionally activated in NSAID treated AML cells. Re-expression of these transcription factors led to activation of GADD45α with induction of apoptosis. Mechanistically, we demonstrate that NSAIDs induce apoptosis in AML through a novel pathway involving increased expression of AP-1 heterodimers, which by itself is sufficient to induce GADD45α expression with consecutive activation of JNK and induction of apoptosis.
Overall design HL-60 and THP-1 AML cells were treated with 100 µM Diclofenac or DMSO as control for 48 hours. Each experiment was performed in duplicate. After this treatment total RNA of the cells was harvested and analysed by means of gene expression profiling with the Affymetrix HU-133A array.
Contributor(s) Singh R, Koch A
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Submission date Mar 25, 2011
Last update date Dec 06, 2018
Contact name Ingmar Bruns
Phone +49-211-81-17736
Fax +49-211-81-18853
Organization name University of Düsseldorf
Department Hematology, Oncology and Clinical Immunology
Lab Experimental Hematology
Street address Moorenstr. 5
City Düsseldorf
State/province NRW
ZIP/Postal code 40225
Country Germany
Platforms (1)
GPL571 [HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array
Samples (8)
GSM697692 DMSO treated HL60 cells, biological replicate 1
GSM697693 DMSO treated HL60 cells, biological replicate 2
GSM697694 DMSO treated THP-1 cells, biological replicate 1
BioProject PRJNA139543

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Supplementary file Size Download File type/resource
GSE28185_RAW.tar 16.5 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table

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