Cancer letters, 2019-02, Vol.442, p.233-241
2019
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- Autor(en) / Beteiligte
- Titel
- Myeloid-derived suppressor cells induce multiple myeloma cell survival by activating the AMPK pathway
- Ist Teil von
- Cancer letters, 2019-02, Vol.442, p.233-241
- Ort / Verlag
- Ireland: Elsevier B.V
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Multiple Myeloma (MM) is an incurable malignancy of terminally differentiated plasma cells, which are predominantly localized in the bone marrow. Myeloid-derived suppressor cells (MDSC) are described to promote MM progression by immunosuppression and induction of angiogenesis. However, their direct role in drug resistance and tumor survival is still unknown. In this study, we performed co-culture experiments of myeloma cells with 5TMM derived MDSC in vitro, leading to increased survival and proliferation of MM cells. Co-culture experiments resulted in MDSC-induced AMPK phosphorylation in MM cells, which was associated with an increase in the anti-apoptotic factors MCL-1 and BCL-2, and the autophagy-marker LC3II. In addition, 5TMM cells inoculated in mice showed a clear upregulation of AMPK phosphorylation in vivo. Targeting the AMPK pathway by Compound C resulted in apoptosis of human myeloma cell lines, primary MM cells and 5TMM cells. Importantly, we observed that the tumor-promoting effect of MDSC was partially mediated by AMPK activation. In conclusion, our data clearly demonstrate that MDSC directly increase the survival of MM cells, partially through AMPK activation, identifying this pathway as a new target in the treatment of MM patients. •Myeloid-derived suppressor cells (MDSC) favor Multiple Myeloma (MM) cell survival•In vivo MDSC depletion (5FU) in combination with bortezomib, reduced tumor load•MDSC induce AMPK phosphorylation, MCL-1 and BCL-2 expression in MM cells•AMPK inhibition reduces MM cell survival in the presence of MDSC•AMPK targeting induced apoptosis of human myeloma cell lines and patients samples
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0304-3835eISSN: 1872-7980DOI: 10.1016/j.canlet.2018.11.002Titel-ID: cdi_hal_primary_oai_HAL_hal_01980419v1
- Format
- –
- Schlagworte
- Activation, AMP-Activated Protein Kinases - antagonists & inhibitors, AMP-Activated Protein Kinases - genetics, AMP-Activated Protein Kinases - metabolism, Angiogenesis, Animals, Antineoplastic Agents - pharmacology, Apoptosis, Autophagy, Bcl-2 protein, Bone marrow, Cancer, Cell culture, Cell cycle, Cell Line, Tumor, Cell lines, Cell Proliferation, Cell Survival, Coculture Techniques, Cytokines, Drug resistance, Drug Resistance, Neoplasm, Enzyme Activation, Genetics, Hematology, Humans, Immunosuppression, Life Sciences, Malignancy, Mcl-1 protein, Mice, Inbred C57BL, Microtubule-Associated Proteins - metabolism, Multiple myeloma, Multiple Myeloma - drug therapy, Multiple Myeloma - enzymology, Multiple Myeloma - genetics, Multiple Myeloma - pathology, Myeloid Cell Leukemia Sequence 1 Protein - metabolism, Myeloid-Derived Suppressor Cells - metabolism, Paracrine Communication - drug effects, Phagocytosis, Phosphorylation, Plasma cells, Protein Kinase Inhibitors - pharmacology, Proto-Oncogene Proteins c-bcl-2 - metabolism, Signal Transduction, Software, Suppressor cells, Tumor cell lines, Tumor Cells, Cultured