Grupo Multidisciplinar de Oncología Traslacional, Institut Universitari d'Investigació en Ciències de la Salut, Universitat de les Illes Balears, Palma, España.
Instituto de Investigació Sanitaria Illes Balears, Palma, España.
J Cell Physiol. 2018 Aug;233(8):6067-6076. doi: 10.1002/jcp.26443. Epub 2018 Mar 6.
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（SIRT3）是主要的线粒体去乙酰化酶，通过靶向几种关键蛋白（如参与线粒体功能和抗氧化防御的蛋白）来调节 ROS 水平。这样，SIRT3 可以平衡 ROS 的产生和清除，并促进细胞存活。本研究旨在分析 SIRT3 沉默对 SW620 结肠癌细胞系抗氧化反应的影响，以及这种干预是否可以提高奥沙利铂（一种常用于治疗结肠癌的常用药物）的疗效。为此，我们获得了 SIRT3 敲低的 SW620 稳定克隆，并确定了 ROS 水平和产生、几种抗氧化酶的水平、细胞活力和细胞凋亡等参数。结果表明，SIRT3 沉默后，ROS 水平和产生均增加，抗氧化酶基因表达显著降低。此外，锰超氧化物歧化酶的水平和酶活性降低。SIRT3 敲低与奥沙利铂治疗联合使用进一步增加了 ROS 的产生和细胞凋亡，降低了细胞活力。最后，结肠癌患者的生存曲线表明 SIRT3 的表达与预后不良有关。总之，SIRT3 可能是结肠癌的一个靶点，因为它调节抗氧化反应，其敲低可提高奥沙利铂治疗的疗效。
