Targeting SOD1 reduces experimental non–small-cell lung cancer

Abstract

Approximately 85% of lung cancers are non-small-cell lung cancers (NSCLCs), which are often diagnosed at an advanced stage and associated with poor prognosis. Currently, there are very few therapies available for NSCLCs due to the recalcitrant nature of this cancer. Mutations that activate the small GTPase KRAS are found in 20% to 30% of NSCLCs. Here, we report that inhibition of superoxide dismutase 1 (SOD1) by the small molecule ATN-224 induced cell death in various NSCLC cells, including those harboring KRAS mutations. ATN-224-dependent SOD1 inhibition increased superoxide, which diminished enzyme activity of the antioxidant glutathione peroxidase, leading to an increase in intracellular hydrogen peroxide (H 2 O 2 ) levels. We found that ATN-224-induced cell death was mediated through H 2 O 2 -dependent activation of P38 MAPK and that P38 activation led to a decrease in the antiapoptotic factor MCL1, which is often upregulated in NSCLC. Treatment with both ATN-224 and ABT-263, an inhibitor of the apoptosis regulators BCL2/BCLXL, augmented cell death. Furthermore, we demonstrate that ATN-224 reduced tumor burden in a mouse model of NSCLC. Our results indicate that antioxidant inhibition by ATN-224 has potential clinical applications as a single agent, or in combination with other drugs, for the treatment of patients with various forms of NSCLC, including KRAS-driven cancers. IntroductionLung cancer is the leading cause of cancer deaths in the United States and worldwide. Non-small-cell lung cancers (NSCLCs) represent 80% of all lung cancers and are often diagnosed at an advanced stage with poor prognosis. Adenocarcinoma, a subtype of NSCLC, is the most common form of lung cancer and is characterized by activating mutations in the KRAS proto-oncogene in 20% to 30% of cases and by inactivating mutations in the tumor suppressor TP53 in 50% of cases (1).With the goal of identifying new therapies for NSCLCs, a largescale chemical screen recently identified a small molecule that selectively induced cell death in oncogenic KRAS-driven (KRAS onc -driven) cancer cells compared with normal cells. The small molecule induced cell death by increasing intracellular ROS (2). However, the mechanism by which ROS was induced and caused cell death has not yet been established. Also, it is known that oncogenic-driven cancer cells generate increased ROS as byproducts of their augmented metabolism to promote and maintain tumorigenicity (3-5). Since high levels of ROS can induce cell death (2, 6), cancer cells adapt to ROS stress by upregulating intracellular antioxidant proteins (7-10) in order to maintain ROS levels that allow protumorigenic signaling without inducing cell death. This reliance on antioxidants potentially makes cancer cells selectively vulnerable to antioxidant inhibition, as nontransformed cells generate lower basal levels of ROS and are therefore less dependent on their detoxification. In fact, studies have shown that disabling antioxidant mechanisms triggers ROS-mediated cell death in a variety of cancer cell ty...

Cancer, Oxidative Stress, and Metastasis

“…The finding that distant metastasis is limited by oxidative stress is not an artifact of xenotransplantation into immunocompromised mice as similar results were observed in immunocompetent mice with autochthanous melanomas: Treatment with NAC or vitamin E promoted distant metastasis without affecting the growth of subcutaneous tumors (Le Gal et al 2015). Consistent with this, cancer cells depend on NRF2 (Wang et al 2016), thioredoxinlike 2 (Qu et al 2011), superoxide dismutase (Kamarajugadda et al 2013;Glasauer et al 2014), and glutamate cysteine ligase (the rate-limiting step of glutathione synthesis) (Nguyen et al 2016) to survive during metastasis.…”

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

“…A number of observations potentially implicate SOD1 in tumorigenesis (114). For example, increased SOD1 expression was found in a panel of breast cancer cell lines (113); overexpression of SOD1 promotes growth of lung cancer cells (152); and inhibition of SOD1 induces cell death in the lung carcinoma cell line A549 (49). Mutation of the SOD1 succinylation site inhibited the growth of lung cancer cells (88), suggesting a role for SIRT5-mediated SOD1 desuccinylation and activation in promoting tumorigenesis.…”

Relationships between chronic obstructive pulmonary disease and lung cancer: biological insights

“…In fact, proteins such as cofilin (34), vimentin (115), and alpha-1-antitrypsin (116,117) were also shown to be more oxidized in the normal epithelium of the airways distant to the neoplasm in patients with LC (25), and their function was altered as a result of the oxidative posttranslational modifications, which may contribute to lung destruction and emphysema (116,117).…”

“…The conclusions from these findings were that SOD2 may be a key survival mechanism for the cancer cells to proliferate in the tumors. In fact, another investigation (34) demonstrated that inhibition of SOD activity reduced tumor burden in mice and promoted cell death in several NSCLC lines of cells. Furthermore, SOD2 was also shown to favor cell migration and invasiveness of tumors in other investigations (117,118).…”

“…For instance, oxidative and nitrosative stress as a result of reactive oxygen and nitrogen species (ROS and RNS, respectively) were shown to favor carcinogenesis through the activation of cellular processes that result in neoplastic transformation or the induction of DNA mutations (32). Other investigations have also demonstrated the contribution of oxidative damage, inflammatory events, and tumor microenvironment to lung carcinogenesis in patients and animal models (19,20,(25)(26)(27)(28)(29)(30)(31)(33)(34)(35)(36)(37).…”