Department of Microbiology and Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul 08758, Korea.
Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 08758, Korea.
Int J Mol Sci. 2020 Dec 16;21(24):9575. doi: 10.3390/ijms21249575.
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.
自然杀伤 (NK) 细胞因其强大的细胞毒性活性而成为癌症免疫治疗的合适靶点。为了最大限度地提高癌症免疫治疗的疗效，需要确定佐剂。白藜芦醇是一种研究得很好的多酚，具有多种潜在的健康益处，包括抗肿瘤作用。我们之前发现白藜芦醇是 NK 细胞的增强剂，这表明它可以作为癌症免疫治疗的佐剂。然而，白藜芦醇激活 NK 细胞的分子机制尚不清楚。本研究旨在确定这一机制。为此，我们使用 Western blot、实时聚合酶链反应、途径抑制剂、蛋白质/DNA 阵列和细胞毒性分析研究了 NK 细胞中的相关途径。我们证实了白藜芦醇和白细胞介素 (IL)-2 协同增强 NK 细胞细胞毒性活性的作用。白藜芦醇通过调节磷酸酶和张力蛋白同源物 (PTEN) 和核糖体蛋白 S6 激酶β-1 (S6K1) 来激活 Akt，从而调节雷帕霉素靶蛋白 (mTOR) 复合物 2 (mTORC2)。此外，白藜芦醇介导的 NK 细胞激活比 Akt 途径更依赖于 mTOR 途径。重要的是，白藜芦醇增加了 Akt 和 mTORC2 的下游转录因子 c-Myb 的表达。此外，c-Myb 对于白藜芦醇与 IL-2 联合诱导的 NK 细胞激活是必不可少的。我们的结果表明，白藜芦醇通过 Akt 和 mTORC2 介导的 c-Myb 上调激活 NK 细胞。
