Metformin promotes antitumor activity of NK cells via overexpression of miRNA-150 and miRNA-155

Andjela R Petrovic; Ivan P Jovanovic; Milena M Jurisevic; Marina Z Jovanovic; Marina M Jovanovic; Sladjana P Pavlovic; Nebojsa N Arsenijevic; Gordana M Supic; Danilo V Vojvodic; Milan M Jovanovic; Nevena M Gajovic

Metformin promotes antitumor activity of NK cells via overexpression of miRNA-150 and miRNA-155

Am J Transl Res. 2023 Apr 15;15(4):2727-2737. eCollection 2023.

Affiliations

¹ Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac Svetozara Markovica 69, Kragujevac 34000, Serbia.
² Department of Pharmacy, Faculty of Medical Sciences, University of Kragujevac Svetozara Markovica 69, Kragujevac 34000, Serbia.
³ Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac Svetozara Markovica 69, Kragujevac 34000, Serbia.
⁴ Institute for Medical Research, Military Medical Academy Crnotravska 17, Belgrade 11000, Serbia.
⁵ Medical Faculty of Military Medical Academy, University of Defense Crnotravska 17, Belgrade 11000, Serbia.
⁶ Department of Abdominal Surgery, Military Medical Academy Crnotravska 17, Belgrade 11000, Serbia.

PMID: 37193182
PMCID: PMC10182535

Abstract

Objectives: Metformin, an oral anti-diabetic drug, is known to possess a powerful antitumor effect by modulating the tumor-immune interaction. The precise influence of metformin on natural killer (NK) cells, a crucial innate immunity player, is not completely understood. In our study, analyses of the effect of metformin on the NK cell functional phenotype were performed, and the potential mechanisms underlying it were investigated.

Methods: BALB/C wild type mice were treated with metformin, and the functional phenotype of splenocytes and potential underlying mechanisms were investigated.

Results: Metformin significantly boosts NK cell cytotoxicity and the percentage of NKp46⁺, FasL⁺, and interferon (IFN)-γ⁺ NK cells while decreasing interleukin (IL)-10 producing NK cells. Our research also demonstrated that the simultaneous administration of metformin and 1-methyl-DL-tryptophan (1-MT), a specific inhibitor of indoleamine 2,3-dioxygenase (IDO), significantly increased the NK cells synthesis of IFN-γ, IL-17, perforin, and FasL and NKp46 expression. These findings imply that metformin potentiates NK cell cytotoxicity through mechanisms other than IDO blockade. Metformin administration strongly increased the expression of immunostimulatory microRNA (miRNA)-150 and miRNA-155, while decreasing the expression of immunosuppressive miRNA-146a.

Conclusions: These findings suggest that metformin can directly potentiate NK cell activation and cytotoxicity. This research may contribute to dissecting key mechanisms of metformin exerting antitumor activity to advance the use of metformin as an antitumor agent.

Keywords: Metformin; NK cell; cancer surveillance; immunotherapy; indoleamine 2,3-dioxygenase; microRNA.