Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Miaoli, Taiwan.
J Cell Biochem. 2014 Feb;115(2):328-39. doi: 10.1002/jcb.24667.
Areca chewing is an important environmental risk factor for development of oral premalignant lesions and cancer. Epidemiological evidence indicates that areca chewing is tightly linked to oral carcinogenesis. However, the pathogenetic impacts of areca nut extract (ANE) on normal human oral keratinocytes (HOKs) are unclear and possibly involve oxidative stress via redox imbalance. Sirtuin 3 (SIRT3) is a member of the sirtuin family of proteins that play an important role in regulating cellular reactive oxygen species (ROS) production. Recent studies have confirmed that ANE and other areca ingredients can induce ROS. In this study, we examined the role of SIRT3 in the regulation of ANE-induced ROS in HOK cells. We examined HOK cell viability following treatment with various ANE concentrations. ANE-induced cytotoxicity increased in a dose-dependent manner and was approximately 48% at a concentration of 50 μg/ml after 24 h. SIRT3 expression and enzyme activity were up-regulated in HOK cells by ANE-induced oxidative stress. Additionally, we identified that SIRT3 controls the enzymatic activity of mitochondrial proteins, such as forkhead box O3a (Foxo3a) transcription factor and antioxidant-encoding gene superoxide dismutase 2 (SOD2), by deacetylation in HOK cells. Moreover, SIRT3-mediated deacetylation and activation of Foxo3a promotes nuclear localization in vivo. These findings suggest that SIRT3 is an endogenous negative regulator in response to ANE-induced oxidative stress and demonstrate an essential role for redox balance in HOK cells.
咀嚼槟榔是导致口腔癌前病变和癌症的重要环境风险因素。流行病学证据表明，咀嚼槟榔与口腔癌变密切相关。然而，槟榔提取物（ANE）对正常人口腔角质细胞（HOK）的致病影响尚不清楚，其可能涉及通过氧化还原失衡导致的氧化应激。Sirtuin 3（SIRT3）是 Sirtuin 蛋白家族的一员，在调节细胞活性氧（ROS）产生中发挥重要作用。最近的研究证实，ANE 和其他槟榔成分可以诱导 ROS。在这项研究中，我们研究了 SIRT3 在调节 HOK 细胞中 ANE 诱导的 ROS 中的作用。我们检测了不同 ANE 浓度处理后 HOK 细胞的活力。ANE 诱导的细胞毒性呈剂量依赖性增加，在 24 小时后浓度为 50μg/ml 时约为 48%。ANE 诱导的氧化应激使 HOK 细胞中 SIRT3 的表达和酶活性上调。此外，我们发现 SIRT3 通过去乙酰化作用控制 HOK 细胞中线粒体蛋白的酶活性，如叉头框 O3a（Foxo3a）转录因子和抗氧化基因超氧化物歧化酶 2（SOD2）。此外，SIRT3 介导的 Foxo3a 去乙酰化和激活促进了其在体内的核定位。这些发现表明，SIRT3 是 ANE 诱导的氧化应激的内源性负调节剂，并证明了在 HOK 细胞中，氧化还原平衡起着重要作用。
