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.

Original languageEnglish
Pages (from-to)233-241
Number of pages9
JournalCancer Letters
Volume442
Early online date9 Nov 2018
DOIs
Publication statusPublished - 1 Feb 2019

    Research areas

  • Autophagy, Drug resistance, Signal transduction

ID: 40247720