@article{14d5d4775ccb4763a9c8b7b42baf77b3,
title = "Metformin inhibits IL-6 signaling by decreasing IL-6R expression on multiple myeloma cells",
abstract = "IL-6 signaling plays a crucial role in the pathogenesis of a number of diseases, including multiple myeloma, primary amyloidosis, cytokine release syndrome and other inflammatory conditions. It is central for the growth and survival of malignant plasma cells. IL-6R and IL-6ST receptors transduce IL-6 signaling. Molecular mechanisms regulating expression of IL-6R are not well understood and current therapies are based on monoclonal antibody to target IL-6 signaling. Small molecule inhibitors targeting IL-6 signaling are highly desirable. Metformin specifically decreased IL-6R expression which is mediated via AMPK, mTOR, and miR34a. This is a novel finding and adds to existing therapies targeting IL-6 signaling.",
author = "Mishra, {Ameet K.} and David Dingli",
note = "Funding Information: Acknowledgements We would like to thank the estate of R. Staberg through the Department of Development at Mayo Clinic that supported Fig. 7 Metformin decreased IL-6R expression and increased cell death in primary myeloma cells. a Histograms showing cell surface expression of IL-6R and IL-6ST in primary multiple myeloma samples from patients who did not receive metformin (n = 4) and who received metformin treatment (n = 2). Gray, blue, and red shaded histograms represent isotype control, no metformin and metformin group respectively. b Difference in median fluorescence intensity for IL-6R expression between primary multiple myeloma samples from patients who did not receive metformin (n = 4) and those who were on metformin treatment (n = 2). c Difference in median fluorescence intensity for IL-6ST expression between primary multiple myeloma samples from patients who did not receive metformin (n = 4) and who received metformin treatment (n = 2). d Difference in median fluorescence intensity for IL-6R expression between primary multiple myeloma samples in response to vehicle control or metformin treatment for 48 h (n = 24). e Pearson{\textquoteright}s correlation was calculated for average IL-6R median fluorescence intensity (MFI) and fraction of dead cells after metformin treatment (n = 24). MFI for cell surface expression was calculated using flow cytometry. Fraction of dead cells was calculated after estimating number of cells after 48 h of metformin 10 mM treatment using CellTiter glo. f Percentage of dead cells was calculated after 48 h of metformin 10 mM treatment using CellTiter glo (n = 24). Data were normalized to vehicle control. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, and ****P ≤ 0.0001 some of this work. The primary multiple myeloma cell bank at Mayo Clinic is supported by the SPORE: CA186781, The Predolin Foundation and The JABBS Foundation. Publisher Copyright: {\textcopyright} 2019, Springer Nature Limited. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",
year = "2019",
month = nov,
day = "1",
doi = "10.1038/s41375-019-0470-4",
language = "English (US)",
volume = "33",
pages = "2695--2709",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",
number = "11",
}