Insights into the Dichotomous Regulation of SOD2 in Cancer

Abstract

While loss of antioxidant expression and the resultant oxidant-dependent damage to cellular macromolecules is key to tumorigenesis, it has become evident that effective oxidant scavenging is conversely necessary for successful metastatic spread. This dichotomous role of antioxidant enzymes in cancer highlights their context-dependent regulation during different stages of tumor development. A prominent example of an antioxidant enzyme with such a dichotomous role and regulation is the mitochondria-localized manganese superoxide dismutase SOD2 (MnSOD). SOD2 has both tumor suppressive and promoting functions, which are primarily related to its role as a mitochondrial superoxide scavenger and H2O2 regulator. However, unlike true tumor suppressor- or onco-genes, the SOD2 gene is not frequently lost, or rarely mutated or amplified in cancer. This allows SOD2 to be either repressed or activated contingent on context-dependent stimuli, leading to its dichotomous function in cancer. Here, we describe some of the mechanisms that underlie SOD2 regulation in tumor cells. While much is known about the transcriptional regulation of the SOD2 gene, including downregulation by epigenetics and activation by stress response transcription factors, further research is required to understand the post-translational modifications that regulate SOD2 activity in cancer cells. Moreover, future work examining the spatio-temporal nature of SOD2 regulation in the context of changing tumor microenvironments is necessary to allows us to better design oxidant- or antioxidant-based therapeutic strategies that target the adaptable antioxidant repertoire of tumor cells.

l-Carnitine counteracts in vitro fructose-induced hepatic steatosis through targeting oxidative stress markers

“…LC increased SOD2 protein concentration compared to both CNT and F, but its effect is not enough to counteract F presence, supporting the hypothesis that other AMPK-independent pathways are at stake. This evidences agrees with the dichotomous SOD2 regulation described in carcinogenic cells, like HepG2 cell line [38] and support our date showing that F seems to act on SOD2 through both AMPK-dependent and -independent manner.…”

Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells

“…In addition, the SIRT3/FOXO3a/SOD2 axis is upregulated as part of the mtUPR and necessary for breast cancer metastasis [25, 35]. Moreover, we and others have demonstrated that SOD2 is required by metastatic cells as an adaptation to oxidative stress, for the maintenance of mitochondrial fidelity, and as a regulator of mitochondria redox signaling [20, 36–38].…”

“…Moreover, several studies have demonstrated that SIRT3 knock-down promotes proliferation and tumorigenesis in tumor models of breast [12, 18], mantle cell lymphoma [19] and liver cancer [16], promoting investigators to initially characterize SIRT3 as a tumor suppressor. However, it is becoming increasingly clear that the role of SIRT3 in tumor biology is complex [17, 20, 21]. Pro-tumorigenic properties of SIRT3 have conversely been reported in oral squamous cell carcinoma [22], and colorectal cancer [23], with increased SIRT3 expression being associated with poor outcome in colon and non-small cell lung cancer patients [17].…”

Melatonin Enhances Palladium-Nanoparticle-Induced Cytotoxicity and Apoptosis in Human Lung Epithelial Adenocarcinoma Cells A549 and H1229

“…Similarly, PdNPs + MLT decreased the levels of CAT and SOD, which had a significant effect on the rate constant of H 2 O 2 removal. Additionally, manganese superoxide dismutase (MnSOD), which is involved in ROS homeostasis, exhibits tumor-suppressive and cancer-promoting properties [75]. A reduced level of MnSOD in A431-P and A431-III cells has been shown to promote the metastatic ability of cancer cells [76].…”