Rac1 signaling protects monocytic AML cells expressing the MLL-AF9 oncogene from caspase-mediated apoptotic death
| Autor: | Friedrich Wartlick, Christian Henninger, Bernd Kaina, C. Hinterleitner, Johannes Huelsenbeck, Anne Schorr, Gerhard Fritz |
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| Rok vydání: | 2013 |
| Předmět: |
rac1 GTP-Binding Protein
Cancer Research Oncogene Proteins Fusion HL60 Clinical Biochemistry T-cell leukemia Pharmaceutical Science Apoptosis Biology Jurkat cells Monocytes chemistry.chemical_compound Cell Line Tumor hemic and lymphatic diseases Survivin medicine Humans DNA Breaks Double-Stranded Acute monocytic leukemia Pharmacology Oncogene Biochemistry (medical) Nuclear Proteins Myeloid leukemia Cell Biology medicine.disease Molecular biology XIAP chemistry Caspases Leukemia Monocytic Acute Cancer research Myeloid-Lymphoid Leukemia Protein Signal Transduction |
| Zdroj: | Apoptosis. 18:963-979 |
| ISSN: | 1573-675X 1360-8185 |
| DOI: | 10.1007/s10495-013-0842-6 |
| Popis: | We investigated the relevance of signaling mechanisms regulated by the Ras-homologous GTPase Rac1 for survival of acute myeloid leukemia (AML) cells harbouring the MLL-AF9 oncogene due to t(9;11)(p21;q23) translocation. Monocytic MLL-AF9 expressing cells (MM6, THP-1) were hypersensitive to both small-molecule inhibitors targeting Rac1 (EHT 1864, NSC 23766) (IC50EHT ~12.5 μM) and lipid lowering drugs (lovastatin, atorvastatin) (IC50Lova ~7.5 μM) as compared to acute myelocytic leukemia (NOMO-1, HL60) and T cell leukemia (Jurkat) cells (IC50EHT >30 μM; IC50Lova >25 μM). Hypersensitivity of monocytic cells following Rac1 inhibition resulted from caspase-driven apoptosis as shown by profound activation of caspase-8,-9,-7,-3 and substantial (~90 %) decrease in protein expression of pro-survival factors (survivin, XIAP, p-Akt). Apoptotic death was preceded by S139-posphorylation of histone H2AX (γH2AX), a prototypical surrogate marker of DNA double-strand breaks (DSBs). Taken together, abrogation of Rac1 signaling causes DSBs in acute monocytic leukemia cells harbouring the MLL-AF9 oncogene, which, together with downregulation of survivin, XIAP and p-Akt, results in massive induction of caspase-driven apoptotic death. Apparently, Rac1 signaling is required for maintaining genetic stability and maintaining survival in specific subtypes of AML. Hence, targeting of Rac1 is considered a promising novel strategy to induce lethality in MLL-AF9 expressing AML. |
| Databáze: | OpenAIRE |
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