Superoxide dismutase 1 (SOD1) is a target for a small molecule identified in a screen for inhibitors of the growth of lung adenocarcinoma cell lines

Somwar, Romel; Erdjument‐Bromage, Hediye; Larsson, Erik; Shum, David; Lockwood, William W.; Yang, Guangli; Sander, Chris; Ouerfelli, Ouathek; Tempst, Paul; Djaballah, Hakim; Varmus, Harold

doi:10.1073/pnas.1113554108

Cited by 128 publications

(131 citation statements)

References 26 publications

(26 reference statements)

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“…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.…”

Section: Metabolic Targets Of Sirt5mentioning

confidence: 99%

“…Studies from several groups indicate an important role of SOD1 in tumor initiation and progression (114). SOD1 is overexpressed in many types of cancer cells (113,152), and its activity may be essential for limiting ROS levels to a level that is consistent with robust cellular proliferation. In this regard, a recent study by Lin et al found that succinylation of SOD1 leads to decreases in its activity (88).…”

Section: Fig 6 Overview Of Interplay Between Mitochondrialmentioning

confidence: 99%

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Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Kumar

Lombard²

2015

Antioxidants & Redox Signaling

120

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Significance: Maintenance of metabolic homeostasis is critical for cellular and organismal health. Proper regulation of mitochondrial functions represents a crucial element of overall metabolic homeostasis. Mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5) play pivotal roles in promoting this homeostasis by regulating numerous aspects of mitochondrial metabolism in response to environmental stressors. Recent Advances: New work has illuminated multiple links between mitochondrial sirtuins and cancer. SIRT5 has been shown to regulate the recently described post-translational modifications succinyl-lysine, malonyllysine, and glutaryl-lysine. An understanding of these modifications is still in its infancy. Enumeration of SIRT3 and SIRT5 targets via advanced proteomic techniques promises to dramatically enhance insight into functions of these proteins. Critical Issues: In this review, we highlight the roles of mitochondrial sirtuins and their targets in cellular and organismal metabolic homeostasis. Furthermore, we discuss emerging roles for mitochondrial sirtuins in suppressing and/or promoting tumorigenesis, depending on the cellular and molecular context. Future Directions: Currently, hundreds of potential SIRT3 and SIRT5 molecular targets have been identified in proteomic experiments. Future studies will need to validate the major targets of these enzymes, and elucidate how acetylation and/or acylation modulate their functionality. A great deal of interest exists in targeting sirtuins pharmacologically; this endeavor will require development of sirtuin-specific modulators (activators and inhibitors) as potential treatments for cancer and metabolic disease. Antioxid.

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Section: Metabolic Targets Of Sirt5mentioning

confidence: 99%

Section: Fig 6 Overview Of Interplay Between Mitochondrialmentioning

confidence: 99%

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Kumar

Lombard²

2015

Antioxidants & Redox Signaling

120

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“…Furthermore, SOD1 was shown to be expressed at higher levels in lung adenocarcinomas compared with the levels seen in normal lungs (15), making it an attractive therapeutic target in lung cancer. SOD1 converts superoxide to hydrogen peroxide (H 2 O 2 ) in the cytosol, the nucleus, and the intermembrane space of the mitochondria.…”

Section: Introductionmentioning

confidence: 99%

“…Varmus and colleagues (15) used an unbiased small-molecule screen and identified the copper-zinc-dependent enzyme and ROS regulator superoxide dismutase 1 (SOD1) as a target for inhibitors of the growth of both KRAS-and EGFR-mutant lung adenocarcinoma cells in vitro. Furthermore, SOD1 was shown to be expressed at higher levels in lung adenocarcinomas compared with the levels seen in normal lungs (15), making it an attractive therapeutic target in lung cancer.…”

Section: Introductionmentioning

confidence: 99%

Targeting SOD1 reduces experimental non–small-cell lung cancer

Glasauer¹,

Sena²,

Diebold³

et al. 2013

J. Clin. Invest.

175

155

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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...

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“…Superoxide dismutase 1 (SOD1), a cellular stress regulator, catalyzes the conversion of superoxide ion (O 2 − ) into H 2 O 2 and O 2 to maintain low levels of Reactive Oxygen Species (ROS). Overexpression of SOD1 has been reported to induce cell proliferation without affecting cell cycle progression and lower the apoptosis of lung carcinoma cell lines (H358 and H1975 cells) which promotes growth by increasing survival [31]. Regulation of cellular process, such as cell proliferation and cell death, is of imminence importance in designing of efficient bioprocess and hence identification of microvesicular proteome is of obvious importance.…”

Section: Functional Analysis Of Microvesicular Proteinsmentioning

confidence: 99%

Exploring Packaged Microvesicle Proteome Composition of Chinese Hamster Ovary Secretome

2016

J Bioprocess Biotech

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Superoxide dismutase 1 (SOD1) is a target for a small molecule identified in a screen for inhibitors of the growth of lung adenocarcinoma cell lines

Cited by 128 publications

References 26 publications

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Targeting SOD1 reduces experimental non–small-cell lung cancer

Exploring Packaged Microvesicle Proteome Composition of Chinese Hamster Ovary Secretome

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