Abstract
Natural killer (NK) cells are suitable targets for cancer immunotherapy owing to their potent cytotoxic activity. To maximize the therapeutic efficacy of cancer immunotherapy, adjuvants need to be identified. Resveratrol is a well-studied polyphenol with various potential health benefits, including antitumor effects. We previously found that resveratrol is an NK cell booster, suggesting that it can serve as an adjuvant for cancer immunotherapy. However, the molecular mechanism underlying the activation of NK cells by resveratrol remains unclear. The present study aimed to determine this mechanism. To this end, we investigated relevant pathways in NK cells using Western blot, real-time polymerase chain reaction, pathway inhibitor, protein/DNA array, and cytotoxicity analyses. We confirmed the synergistic effects of resveratrol and interleukin (IL)-2 on enhancing the cytolytic activity of NK cells. Resveratrol activated Akt by regulating Mammalian Target of Rapamycin (mTOR) Complex 2 (mTORC2) via phosphatase and tensin homolog (PTEN) and ribosomal protein S6 kinase beta-1 (S6K1). Moreover, resveratrol-mediated NK cell activation was more dependent on the mTOR pathway than the Akt pathway. Importantly, resveratrol increased the expression of c-Myb, a downstream transcription factor of Akt and mTORC2. Moreover, c-Myb was essential for resveratrol-induced NK cell activation in combination with IL-2. Our results demonstrate that resveratrol activates NK cells through Akt- and mTORC2-mediated c-Myb upregulation.
Highlights
Natural killer (NK) cells are innate immune lymphocytes that play a key role in the first line of defense against pathogens and cancer [1]
Cell-meNdKiactedllsiamremeunndowtheedrawpiythcpaontebnet ceyntohlaynticceadctbivyityimagmauinnset tustmimorusl,aanntds,thseucehfficaascycyotfoNkiKneceslla-nd anmtibedoidaitesd[i4m].mIunntohthisersatupydyc,anwbeefeonuhnadnctehdatbryeismvemruatnreolstsimhouwlaendts,assuycnhearsgcisyttiockeinffeescat nind aconmtibboidniaetsion with IL-2, IL-12, and IL-15 on IFN-γ secretion; a synergistic effect on the cytolytic activity of NK cells was only observed in combination with IL-2 (Figure 1)
We demonstrated that resveratrol activates Akt by regulating mTORC2 via phosphatase and tensin homolog (PTEN) and S6 kinase beta-1 (S6K1) (Figures 2 and 3)
Summary
Natural killer (NK) cells are innate immune lymphocytes that play a key role in the first line of defense against pathogens and cancer [1]. Clinical studies have exposed the limitations associated with using NK cells, such as their low treatment efficacy and response rate and resistance to immunotherapies [16,17,18] To overcome these limitations, researchers are actively searching for new drug candidates that can. We further investigated the effect of resveratrol on the expression of c-Myb. As shown in Figure 5b,c, IL-2 appeared to increase the mRNA and protein expression levels of c-Myb. As expected, resveratrol significantly increased the level of c-Myb expression compared with that induced by NK cell activity [39,40]. We investiga6teofd13whether resveratrol-induced c-Myb activation was dependent on the Akt and mTOR pathways. Asterisks indicate statistical significance using one-way ANOVA: * p < 0.05, *** p < 0.001, ns: not significant (p > 0.05)
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