Journal
APOPTOSIS
Volume 16, Issue 9, Pages 889-901Publisher
SPRINGER
DOI: 10.1007/s10495-011-0624-y
Keywords
AML; NSAID; GADD45 alpha; Growth arrest; Apoptosis; AP-1
Categories
Funding
- Leukamie Liga e.V. Dusseldorf, Germany
- Forschungskommission of the Heinrich-Heine-University, Dusseldorf, Germany
- Deutsche Krebshilfe
- European Association of Hematology (EHA)
- Department of Defense [PC051217, OC0060439]
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Acute myeloid leukemia is a heterogeneous disease with varying genetic and molecular pathologies. Non-steroidal anti-inflammatory drugs (NSAIDs) have been proven to possess significant anti-proliferative potential in various cancer cells in vitro and in vivo. Hence, treatment with these agents can be utilized to study disease specific anti-proliferative pathways. In this study, a total number of 42 bone marrow derived CD34(+) selected de novo AML patient samples and the AML cell lines THP-1 and HL-60 were treated with the NSAIDs Sulindac sulfide and Diclofenac. We analyzed viability, apoptosis, differentiation and addressed the molecular mechanisms involved. We found a consistent induction of apoptosis and to some extent an increased myeloid differentiation capacity in NSAID treated AML cells. Comprehensive protein and gene expression profiling of Diclofenac treated AML cells revealed transcriptional activation of GADD45 alpha and its downstream MAPK/JNK pathway as well as increased protein levels of the caspase-3 precursor. This pointed towards a role of the c-Jun NH2-terminal kinase (JNK) in NSAID mediated apoptosis that we found indeed to be 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 and re-expression of these transcription factors led to activation of GADD45 alpha 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 GADD45 alpha expression with consecutive activation of JNK and induction of apoptosis.
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