ArticleJournal of cancer research and clinical oncology2013
The E3 ubiquitin ligase TRAF6 inhibits LPS-induced AKT activation in FLT3-ITD-positive MV4-11 AML cells.
Article in Journal of cancer research and clinical oncology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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4 citing papers in PubMed, 11 citations in OpenAlex.
- The structure and functions of TRAF families and recent advances of TRAFs in leukemia.Frontiers in oncology · 2026Review
- Benzoyl-xanthone derivative induces apoptosis in MCF-7 cells by binding TRAF6.Experimental and therapeutic medicine · 2022Article
- E3 ubiquitin ligases in the acute leukemic signaling pathways.Frontiers in physiology · 2022Review
- Cinchonine induces apoptosis of HeLa and A549 cells through targeting TRAF6.Journal of experimental & clinical cancer research : CR · 2017Article
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Authors and funding
8 authors at 2 institutions in 2 countries.
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No grant is acknowledged in the PubMed record.
Abstract
purposeThe aim of the study was to investigate the activation of the PI3K/AKT (phosphatidylinositol-3-kinase) pathway after stimulation of TLR-4 (Toll-like receptor 4) with LPS (lipopolysaccharide) in FLT3-ITD (internal tandem duplication)-positive AML (acute myeloid leukemia) cells. TRAF6 (tumor necrosis factor receptor-associated factor 6), an E3 ubiquitin ligase, is critically involved in TLR-signaling. Based on the observation that TRAF6 might play a role in AKT phosphorylation, we hypothesized that TRAF6 can enhance the constitutive FLT3-ITD-driven activation of AKT after LPS stimulation. MATERIALS AND
methodsHuman MV4-11 FLT3-ITD cells were silenced for TRAF6 by stable shRNA expression. Western blotting was used to analyze signal transduction by detection of phosphorylated proteins. LPS-induced activation of the NF-κB pathway was ensured by the induction of IκBα expression. To evaluate a potential functional role of TRAF6, we also performed chemosensitivity assays.
resultsIn MV4-11 cells, AKT was activated in response to LPS treatment. Surprisingly, shRNA-mediated knockdown of TRAF6 resulted in a significant increase in basal AKT phosphorylation. By LPS stimulation, the gain of AKT phosphorylation was more pronounced in the TRAF6 knockdown cell line than in the control. In addition, the concentration-dependent induction of apoptosis in response to treatment with the cytostatic drugs cytarabine or daunorubicin was significantly reduced in TRAF6-depleted MV4-11 cells.
conclusionOur data strongly suggest that the E3 ubiquitin ligase TRAF6 plays an important functional role in signal transduction and survival of AML cells. We hypothesize that LPS-mediated stimulation of TLR-4 leads to the induction of NF-κB-mediated signaling. However, TRAF6 might prevent a synergistic activation of the PI3K/AKT pathway after activation of TLR-4 signaling in FLT3-ITD-positive cells.
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