Resveratrol (trans-3,5,4′-trihydroxystilbene) suppresses EL4 tumor growth by induction of apoptosis involving reciprocal regulation of SIRT1 and NF-κB
Resveratrol (trans-3,5,4′-trihydroxystilbene) suppresses EL4 tumor growth by induction of apoptosis involving reciprocal regulation of SIRT1 and NF-κB
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DOI：
10.1002/mnfr.201000576
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发表时间：
2011-08-01
影响因子：
5.2
通讯作者：
Nagarkatti, Prakash S.
中科院分区：
文献类型：
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作者：
Singh, Narendra P.;Singh, Udai P.;Nagarkatti, Prakash S.
范围：了解天然产品和膳食补充剂展示抗癌特性的分子机制至关重要，并可导致药物发现和化学预防。本研究为白藜芦醇(Res)抗EL-4淋巴瘤生长的作用机制提供了新的线索。方法和结果：免疫缺陷NOD/SCID小鼠注射EL-4肿瘤细胞后给予白藜芦醇(100 mg/kg体重)治疗，肿瘤生长延迟，平均生存时间延长。Res通过激活芳香烃受体(AhR)，上调Fas和FasL的表达，在体外诱导EL4细胞的凋亡。FasL单抗阻断Res诱导的EL4细胞的凋亡，caspase和PARP的裂解，细胞色素c的释放，证实了外源性和内源性的细胞凋亡途径的参与。RES还诱导EL4细胞沉默交配型信息调节2同源1(SIRT1)上调和核因子kappaB(NF-kappa B)下调。SiRNA介导的SIRT1在EL4细胞中的表达下调增加了核因子-kappa B的活性，但减少了RES介导的细胞凋亡，提示SIRT1通过阻断核因子-kappaB的激活而在细胞凋亡中发挥重要作用。结论：Res诱导的SIRT1上调可能通过负调控核因子-kappa B促进肿瘤细胞的凋亡，从而抑制肿瘤生长。
Scope: Understanding the molecular mechanisms through which natural products and dietary supplements exhibit anticancer properties is crucial and can lead to drug discovery and chemoprevention. The current study sheds new light on the mode of action of resveratrol (RES), a plant-derived polyphenolic compound, against EL-4 lymphoma growth.Methods and results: Immuno-compromised NOD/SCID mice injected with EL-4 tumor cells and treated with RES (100 mg/kg body weight) showed delayed development and progression of tumor growth and increased mean survival time. RES caused apoptosis in EL4 cells through activation of aryl hydrocarbon receptor (AhR) and upregulation of Fas and FasL expression in vitro. Blocking of RES-induced apoptosis in EL4 cells by FasL mAb, cleavage of caspases and PARP, and release of cytochorme c, demonstrated the participation of both extrinsic and intrinsic pathways of apoptosis. RES also induced upregulation of silent mating type information regulation 2 homolog, 1 (SIRT1) and downregulation of nuclear factor kappa B (NF-kappa B) in EL4 cells. siRNA-mediated downregulation of SIRT1 in EL4 cells increased the activation of NF-kappa B but decreased RES-mediated apoptosis, indicating the critical role of SIRT1 in apoptosis via blocking activation of NF-kappa B.Conclusion: These data suggest that RES-induced SIRT1 upregulation promotes tumor cell apoptosis through negative regulation of NF-kappa B, leading to suppression of tumor growth.