Abstract
Superoxide dismutases (SODs) are important antioxidant enzymes responsible for the elimination of superoxide radical (O(2)(-)). The manganese-containing SOD (Mn-SOD) has been suggested to have tumor suppressor function and is located in the mitochondria where the majority of O(2)(-) is generated during respiration. Although increased reactive oxygen species (ROS) in cancer cells has long been recognized, the expression of Mn-SOD in cancer and its role in cancer development remain elusive. The present study used a human tissue microarray to analyze Mn-SOD expression in primary ovarian cancer tissues, benign ovarian lesions, and normal ovary epithelium. Significantly higher levels of Mn-SOD protein expression were detected in the malignant tissues compared with normal tissues (p < 0.05). In experimental systems, suppression of Mn-SOD expression by small interfering RNA caused a 70% increase of superoxide in ovarian cancer cells, leading to stimulation of cell proliferation in vitro and more aggressive tumor growth in vivo. Furthermore, stimulation of mitochondrial O(2)(-) production induced an increase of Mn-SOD expression. Our findings suggest that the increase in Mn-SOD expression in ovarian cancer is a cellular response to intrinsic ROS stress and that scavenging of superoxide by SOD may alleviate the ROS stress and thus reduce the simulating effect of ROS on cell growth.
Highlights
Reactive oxygen species (ROS)4, such as superoxide (O2Ϫ) and hydrogen peroxide (H2O2), are constantly produced during metabolic processes in all living species
Our findings suggest that the increase in manganese-containing SOD (Mn-SOD) expression in ovarian cancer is a cellular response to intrinsic reactive oxygen species (ROS) stress and that scavenging of superoxide by SOD may alleviate the ROS stress and reduce the simulating effect of ROS on cell growth
The cytosolic copper/ zinc-containing SOD (Cu,Zn-SOD, or SOD1) and the mitochondrial manganese-containing SOD (Mn-SOD, or SOD2) are two essential enzymes responsible for catalyzing the conversion of O2Ϫ to H2O2, which is further eliminated by catalase and peroxidases [7]
Summary
The same study shows low levels of SOD, catalase, vitamin C, and vitamin E in the plasma of the patient blood samples, possibly due to their increased utilization in scavenging lipid peroxides as well as their sequestration by tumor cells [18]. Tissue microarray analysis provides an effective tool for such analyses This new technique was used in the present study to compare the expression of Mn-SOD and Cu,Zn-SOD in primary human ovarian cancer tissues, benign ovarian lesions, and normal tissues. The increased SOD activity decreases superoxide content in the cells and reduces the ROS-mediated stimulation of cell growth If this were the case, Mn-SOD would decrease cancer cell proliferation indirectly through reduction of ROS, unlike conventional tumor suppressors, which usually regulate cell growth and show decreased expression in cancer tissues. Suppression of Mn-SOD expression caused accumulation of ROS, leading to increased cell proliferation in vitro and rapid tumor growth in vivo
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