Sirtuin 3 silencing improves oxaliplatin efficacy through acetylation of MnSOD in colon cancer

Abstract

Sirtuin 3 (SIRT3) is the major mitochondria deacetylase and regulates ROS levels by targeting several key proteins, such as those involved in mitochondrial function and antioxidant defenses. This way, SIRT3 balances ROS production and scavenging and promotes cell survival. The aim of this study was to analyze the effect of SIRT3 silencing on the antioxidant response in SW620 colon cancer cell line, and whether this intervention could improve efficacy of oxaliplatin, a common drug used to treat colon cancer. For this purpose, we obtained stable clones of SW620 with SIRT3 knockdown and determined parameters such as ROS levels and ROS production, levels of several antioxidant enzymes, cell viability, and apoptosis. Results showed that after SIRT3 silencing, both ROS levels and production were increased, and antioxidant enzymes gene expression was significantly reduced. Furthermore, manganese superoxide dismutase levels and enzymatic activity were reduced. Combination of SIRT3 knockdown with oxaliplatin treatment further increased ROS production and apoptosis, reducing cell viability. Finally, survival curves on colon cancer patients suggested that SIRT3 expression is related to a poorer prognosis. In conclusion, SIRT3 could be a target for colon cancer, since it regulates the antioxidant response and its knockdown improves the efficacy of oxaliplatin treatment.

Sirtuin 3 is essential for host defense against Mycobacterium abscessus infection through regulation of mitochondrial homeostasis

“…Previous studies demonstrated that mitochondrial ROS generation is modulated by SIRT3 in a variety of cells [ 26 – – 29 ]. Thus, the mitochondrial redox status was compared between SIRT3 WT and SIRT3 KO BMDMs using MitoSOX Red, a highly selective fluorescent probe for the detection of mitochondrial O 2 − [ 30 ].…”

“…Data represent three independent experiments (c left), and values represent means (± SEM) from three or four independent experiments performed in triplicate (a and b). Previous studies demonstrated that mitochondrial ROS generation is modulated by SIRT3 in a variety of cells [26][27][28][29]. Thus, the mitochondrial redox status was compared between SIRT3 WT and SIRT3 KO BMDMs using MitoSOX Red, a highly selective fluorescent probe for the detection of mitochondrial O 2 − [30].…”

The Roles of Sirtuin Family Proteins in Cancer Progression

“…SIRT3 plays a conflicting role not only in different types of cancer, such as gastric cancer [133,134], lung cancer [49,135,136], and colon cancer [137][138][139][140], but also in malignancies originating from the same types of tissue. SIRT3 has been found to affect tumorigenesis by depleting reactive oxygen species (ROS), modulating metabolism, and regulating proliferative or apoptotic pathways [141].…”

Sirt3 inhibits cerebral ischemia-reperfusion injury through normalizing Wnt/β-catenin pathway and blocking mitochondrial fission

“…Sirtuin 3 (Sirt3), a type of NAD-dependent deacetylase expressed mainly in mitochondria, has recently been reported to have multiple effects on mitochondrial protection in response to several types of stress, such as oxidative stress (Torrens-Mas et al 2018), hyperglycemia (Nassir et al 2018), fatty acid composition (Chabi et al 2018), and myocardial infarction (Hou et al 2015). At the molecular level, Sirt3 protects against p53-mediated mitochondrial damage and neuronal death in a deacetylase activity-dependent manner (Lee et al 2018).…”