STRESS‐Responsive Deacetylase SIRT3 is Up‐Regulated by Areca Nut Extract‐Induced Oxidative Stress in Human Oral Keratinocytes

Abstract

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.

CYP450‐mediated mitochondrial ROS production involved in arecoline N‐oxide‐induced oxidative damage in liver cell lines

“…In addition, co‐treatment with NAC, Trolox, and penicillamine could prevent ARNO‐induced ROS production in the same cell line (Figures ). In fact, similar results have been reported by others . They show that both arecoline and areca nut extract increase ROS production in various cell lines and this effect can be effectively attenuated by antioxidants, including catalase, NAC, and glutathione.…”

“…In fact, similar results have been reported by others. 27,36,40 They show that both arecoline and areca nut extract increase ROS production in various cell lines and this effect can be effectively attenuated by antioxidants, including catalase, NAC, and glutathione. In general, a buildup of ROS in cells may cause damage to DNA, RNA, and proteins, and may cause cell death.…”

Resveratrol regulates mitochondrial reactive oxygen species homeostasis through Sirt3 signaling pathway in human vascular endothelial cells

“…Proteomics research has shown that several subunits of the enzymes in the mitochondrial ETC and TCA cycle have multiple acetylation modification sites, and increased acetylation was observed in Sirt3 −/− tissues, indicating that the enzyme activities may be regulated by Sirt3. 27 , 28 , 29 In addition, mice lacking Sirt3 showed striking hyperacetylation of mitochondrial proteins, which were associated with accelerated development of metabolic syndrome. 30 , 31 , 32 Our current findings suggested that RSV promotes SOD2 deacetylation in mitochondria, which was suppressed by Sirt3 siRNA transfection, suggesting that Sirt3 plays a critical role in RSV-induced deacetylation in endothelial cells.…”

Function of theSIRT3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease

“…Keratinocyte differentiation is known to influence the formation/maintenance of the protective skin barrier (Bause et al ., ; Chen et al ., ). However, dysregulation in the balance of ROS homeostasis is known to impact keratinocyte differentiation.…”