Department of Hematology and Oncology, Kanazawa University Hospital, Kanazawa, Japan.
Cancer Sci. 2013 Jun;104(6):657-62. doi: 10.1111/cas.12141. Epub 2013 Apr 26.
The powerful activating receptor NKG2D is expressed by natural killer (NK) cells and promotes cytotoxic lysis of cancer cells expressing NKG2D ligands (NKG2D-Ls). We report the effective induction of NKG2D-Ls, achieved with the naturally occurring polyphenol resveratrol, in a broad range of leukemia cells. In this study, resveratrol upregulated the NKG2D-Ls MHC class I chain-related proteins MICA and MICB, and UL16-binding proteins ULBP1, ULBP2, and ULBP3 in most of the leukemia cells analyzed. Ligand upregulation induced by resveratrol was impaired by pharmacological and genetic disruption of ataxia-telangiectasia mutated kinase, the main regulator of NKG2D-L expression. Leukemia cells treated with resveratrol were more susceptible to killing by NK cells than untreated cells, and the enhanced cytotoxicity of NK cells was blocked by treatment of NK cells with anti-NKG2D mAbs. Interestingly, resveratrol consistently upregulated the NKG2D receptor expression and enhanced NKG2D-mediated functions in resting NK cells obtained from healthy individuals. Therefore, resveratrol has attractive immunotherapeutic potential.
NKG2D 是一种强大的激活受体，表达于自然杀伤（NK）细胞表面，可促进其识别并杀伤表达 NKG2D 配体（NKG2D-Ls）的肿瘤细胞。我们报告了天然存在的多酚白藜芦醇可有效诱导多种白血病细胞表面 NKG2D-Ls 的表达。在本研究中，白藜芦醇能上调大多数白血病细胞中 NKG2D-Ls MHC Ⅰ类链相关蛋白 MICA 和 MICB，以及 UL16 结合蛋白 ULBP1、ULBP2 和 ULBP3 的表达。白藜芦醇诱导的配体上调作用，可被ataxia-telangiectasia mutated kinase 的药理学和遗传学阻断，后者是 NKG2D-L 表达的主要调控因子。经白藜芦醇处理的白血病细胞比未经处理的细胞更易被 NK 细胞杀伤，而 NK 细胞经抗 NKG2D mAb 处理后，可阻断其增强的细胞毒性。有趣的是，白藜芦醇可稳定地上调来自健康个体的静止 NK 细胞中 NKG2D 受体的表达，并增强其介导的功能。因此，白藜芦醇具有诱人的免疫治疗潜力。
