Extracellular Superoxide Dismutase Induces Mouse Embryonic Fibroblast Proliferative Burst, Growth Arrest, Immortalization, and Consequent <i>In Vivo</i> Tumorigenesis

Castellone, Maria Domenica; Langella, Angela; Cantara, Silvia; Laurila, Juha; Laatikainen, Lilja; Bellelli, Roberto; Pacini, Furio; Salvatore, Marco; Laukkanen, Mikko O.

doi:10.1089/ars.2013.5475

Cited by 26 publications

(60 citation statements)

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“…We previously showed that robust SOD3 over-expression reduced the rate of cell proliferation by causing DNA damage, inducing the DNA-damage response, and activating the downstream p53-p21 signal transduction pathway of TPC1 papillary thyroid cancer cells, which have an intact growth-arrest signaling pathway. Notably, robust SOD3 over-expression also reduced the rate of cell proliferation of anaplastic thyroid cancer 8505c cells, which lack functional growth-arrest signaling [ 5 ]. Therefore, in the current study, we sought novel SOD3–related signal transduction routes and the molecules that could transmit the SOD3-based extracellular signals to the cytoplasmic signaling network.…”

Section: Resultsmentioning

confidence: 99%

“…Notably, both O 2 .- and H 2 O 2 are second messengers in cell signaling [ 2 , 3 ] suggesting that the cellular effects of SOD3 are mediated by the local reduction of the O 2 .- concentration and the simultaneous increase of the H 2 O 2 concentration affecting the activation of the cell membrane-bound receptor tyrosine kinases (RTK), with a consequent impact on downstream growth and migration signaling [ 4 , 5 , 6 ]. Consistent with this hypothesis, several studies have demonstrated that SOD3 regulated growth and survival related signal transduction and gene expression [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ], hence emphasizing the importance of this enzyme in growth regulation. Interestingly, SOD3 expression is mildly upregulated in benign tumor model systems whereas it is downregulated in several cancers and in transformed cell lines [ 12 , 13 ] suggesting that the enzyme might be involved in the initiation of benign hyperplasia.…”

Section: Introductionmentioning

confidence: 99%

“…Based on our recent data SOD3 has a dose-dependent effect on cellular proliferation; low expression levels of SOD3 induce GTP loading on small GTPase proteins, mitogen signaling and cell proliferation, whereas high levels of SOD3 activate the DNA-damage response and the p53-p21 growth arrest pathway [ 5 , 6 ]. Although activation of the p53-p21 signal transduction pathway is likely to play a major role in growth limitation, high-dose SOD3–inhibited proliferation was also observed in anaplastic thyroid cancer cells lacking functional p53 [ 5 ], indicating the existence of additional growth regulatory mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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Extracellular Superoxide Dismutase Regulates the Expression of Small GTPase Regulatory Proteins GEFs, GAPs, and GDI

et al. 2015

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Extracellular superoxide dismutase (SOD3), which catalyzes the dismutation of superoxide anions to hydrogen peroxide at the cell membranes, regulates the cellular growth in a dose-dependent manner. This enzyme induces primary cell proliferation and immortalization at low expression levels whereas it activates cancer barrier signaling through the p53-p21 pathway at high expression levels, causing growth arrest, senescence, and apoptosis. Because previous reports suggested that the SOD3–induced reduction in the rates of cellular growth and migration also occurred in the absence of functional p53 signaling, in the current study we investigated the SOD3-induced growth-suppressive mechanisms in anaplastic thyroid cancer cells. Based on our data, the robust over-expression of SOD3 increased the level of phosphorylation of the EGFR, ERBB2, RYK, ALK, FLT3, and EPHA10 receptor tyrosine kinases with the consequent downstream activation of the SRC, FYN, YES, HCK, and LYN kinases. However, pull-down experiments focusing on the small GTPase RAS, RAC, CDC42, and RHO revealed a reduced level of growth and migration signal transduction, such as the lack of stimulation of the mitogen pathway, in the SOD3 over-expressing cells, which was confirmed by MEK1/2 and ERK1/2 Western blotting analysis. Interestingly, the mRNA expression analyses indicated that SOD3 regulated the expression of guanine nucleotide-exchange factors (RHO GEF16, RAL GEF RGL1), GTPase-activating proteins (ARFGAP ADAP2, RAS GAP RASAL1, RGS4), and a Rho guanine nucleotide-disassociation inhibitor (RHO GDI 2) in a dose dependent manner, thus controlling signaling through the small G protein GTPases. Therefore, our current data may suggest the occurrence of dose-dependent SOD3–driven control of the GTP loading of small G proteins indicating a novel growth regulatory mechanism of this enzyme.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Extracellular Superoxide Dismutase Regulates the Expression of Small GTPase Regulatory Proteins GEFs, GAPs, and GDI

et al. 2015

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“…Although growth promoting effects of EcSOD at lower levels have been shown in a thyroid cancer cell line, PCCL3 [141 142], inhibitory effects of this antioxidant in cells harboring p53 mutations resulted in reductions in cell growth, invasion, and soft agar colony formation [143 144]. Thus, EcSOD may have biphasic effects on tumor progression switching from a tumor promoter during tumorigenesis to a tumor suppresser shortly after transformation.…”

Section: Expression Levels and Effects Of Ecsod In Cancersmentioning

confidence: 99%

Extracellular superoxide dismutase and its role in cancer

Griess

Tom

Domann

et al. 2017

Free Radical Biology and Medicine

150

124

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Reactive oxygen species (ROS) are increasingly recognized as critical determinants of cellular signaling and a strict balance of ROS levels must be maintained to ensure proper cellular function and survival. Notably, ROS is increased in cancer cells. The superoxide dismutase family plays an essential physiological role in mitigating deleterious effects of ROS. Due to the compartmentalization of ROS signaling, EcSOD, the only superoxide dismutase in the extracellular space, has unique characteristics and functions in cellular signal transduction. In comparison to the other two intracellular SODs, EcSOD is a relatively new comer in terms of its tumor suppressive role in cancer and the mechanisms involved are less well understood. Nevertheless, the degree of differential expression of this extracellular antioxidant in cancer versus normal cells/tissues is more pronounced and prevalent than the other SODs. A significant association of low EcSOD expression with reduced cancer patient survival further suggests that loss of extracellular redox regulation promotes a conducive microenvironment that favors cancer progression. The vast array of mechanisms reported in mediating deregulation of EcSOD expression, function, and cellular distribution also supports that loss of this extracellular antioxidant provides a selective advantage to cancer cells. Moreover, overexpression of EcSOD inhibits tumor growth and metastasis, indicating a role as a tumor suppressor. This review focuses on the current understanding of the mechanisms of deregulation and tumor suppressive function of EcSOD in cancer.

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“…According to a number of recent studies, the abovementioned TGFβ paradox is caused by a change in linker region phosphorylation and by TGFβ-mediated activation of canonical non-SMAD pathways, most prominently RAS-ERK signaling (24,27,28,30). This signaling activation increases ROS production (31,32), causing DNA damage and activation of the DNA damage response (33). Mechanistically, TGFβ contributes to tissue fibrosis in chronic inflammation by inducing ROS production, thus creating a favorable microenvironment for cancer cell growth and tumor initiation (34).…”

Section: Tgf-β/smad Signaling As Tumor Suppressor and Tumor Promotermentioning

confidence: 99%

TGF-beta1 WNT and SHH signaling in tumor progression and in fibrotic diseases

Castellone

Laukkanen

2017

Front Biosci

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Activation of resting fibroblasts to myofibroblasts characterizes several physiological and pathological conditions, from wound healing to aggressive metastatic cancers. In tissue damage, including wound healing, fibroblasts are activated in response to injury for a limited period of time to stimulate the healing process. Similar biological mechanisms are maintained in pathological conditions, e.g., scleroderma and cancer, where myofibroblasts persist in producing cytokines and growth factors to drive the development of fibrosis and the progression of disease. Studies characterizing the bi-directional signal transduction pathways between cancer cells and stromal cells have suggested novel druggable targets that may function in both the inhibition of fibrotic reactions in cancer stroma and in the inhibition of fibrotic diseases. In this review, we focus on transforming growth factor beta (TGF-beta), int/Wingless (WNT), and sonic hedgehog (SHH) signal transduction pathways and describe small molecule inhibitors that are used in phase I/II clinical trials to treat fibrosis or fibrotic cancers.

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Extracellular Superoxide Dismutase Induces Mouse Embryonic Fibroblast Proliferative Burst, Growth Arrest, Immortalization, and Consequent In Vivo Tumorigenesis

Cited by 26 publications

References 50 publications

Extracellular Superoxide Dismutase Regulates the Expression of Small GTPase Regulatory Proteins GEFs, GAPs, and GDI

Extracellular Superoxide Dismutase Regulates the Expression of Small GTPase Regulatory Proteins GEFs, GAPs, and GDI

Extracellular superoxide dismutase and its role in cancer

TGF-beta1 WNT and SHH signaling in tumor progression and in fibrotic diseases

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