Resveratrol Activates Natural Killer Cells through Akt- and mTORC2-Mediated c-Myb Upregulation

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.