Extracellular superoxide dismutase suppresses hypoxia-inducible factor-1α in pancreatic cancer

Sibenaller, Zita A.; Welsh, Jessemae L.; Du, Chunling; Witmer, Jordan R; Schrock, Hannah; Du, Juan; Buettner, Garry R.; Goswami, Prabhat C.; Cieslak, John A.; Cullen, Joseph J.

doi:10.1016/j.freeradbiomed.2014.02.002

Cited by 34 publications

(27 citation statements)

References 34 publications

(51 reference statements)

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“…Moreover, VEGF-related genes, such as the gene encoding for VEGFR3 or enzyme affecting HIF1 and VEGF expression, resulted also upregulated in IM-treated tumors (Table 4; ref. 30).…”

Section: Whole Transcriptome Sequencingmentioning

confidence: 99%

Efficacy and Biological Activity of Imatinib in Metastatic Dermatofibrosarcoma Protuberans (DFSP)

Stacchiotti¹,

Pantaleo²,

Negri³

et al. 2015

Clin Cancer Res

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Purpose: To report on imatinib mesylate (IM) in patients with metastatic dermatofibrosarcoma protuberans (DFSP)/fibrosarcomatous (FS)-DFSP and on the impact of the treatment on tumor biology.Experimental design: Ten consecutive patients treated with IM from 2007 to 2015 for a metastatic relapse from DFSP/FS-DFSP were identified. FISH analysis for COL1A1-PDGFB was performed. Two IM-treated and 4 na€ ve FS-DFSP were transcriptionally profiled by RNAseq on HiScanSQ platform. Differential gene expression was analyzed with edgeR (Bioconductor), followed by hierarchical clustering and Principal Component Analysis.Results: All cases featured fibrosarcomatous in the metastasis and retained the COL1A1-PDGFB. Best RECIST response was: 8 partial response, 1 stable disease, and 1 progressive disease. Median progression-free survival was 11 months. Five patients received surgery after IM and all relapsed. IM was restored in 4 patients with a new response. After IM, the most upregulated genes included those encoding for immunoglobulins and those affecting functions and differentiation of endothelial cells. Pathway enrichment analysis revealed upregulation in genes involved in antigen processing and presentation, natural killer-mediated cytotoxicity, and drug and xenobiotics metabolism. Conversely, a significant down-regulation of kinase signaling pathways was detected.Conclusions: All metastatic cases were fibrosarcomatous. Most patients responded to IM, but PFS was shorter than reported in published series which included both DFSP and FS-DFSP. All patients operated after IM had a relapse, suggesting that IM cannot eradicate metastatic cases and that the role of surgery is limited. Transcriptional profile of na€ ve and posttreatment samples pointed the contribution of immune infiltrates in sustaining the response to IM.

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“…Moreover, VEGF-related genes, such as the gene encoding for VEGFR3 or enzyme affecting HIF1 and VEGF expression, resulted also upregulated in IM-treated tumors (Table 4; ref. 30).…”

Section: Whole Transcriptome Sequencingmentioning

confidence: 99%

Efficacy and Biological Activity of Imatinib in Metastatic Dermatofibrosarcoma Protuberans (DFSP)

Stacchiotti¹,

Pantaleo²,

Negri³

et al. 2015

Clin Cancer Res

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“…It also plays an important role in mediating cell adhesion and migration primarily in activation of rat oval cells (Pi et al, 2008). Sod3 has been shown to act as a tumour suppressor in prostate (Kim et al, 2014) and pancreatic cancer (Sibenaller et al, 2014) by modulation of ROS. Alternatively, induction of Ero1l by HIF-1a within a hypoxic microenvironment leads to angiogenesis and improved tumour survival (May et al, 2005).…”

Section: Transcription Factor Binding Site Analysismentioning

confidence: 99%

Transcriptional profiling of rat hypothalamus response to 2,3,7,8-tetrachlorodibenzo-ρ-dioxin

et al. 2015

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In some mammals, halogenated aromatic hydrocarbon (HAH) exposure causes wasting syndrome, defined as significant weight loss associated with lethal outcomes. The most potent HAH in causing wasting is 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD), which exerts its toxic effects through the aryl hydrocarbon receptor (AHR). Since TCDD toxicity is thought to predominantly arise from dysregulation of AHR-transcribed genes, it was hypothesized that wasting syndrome is a result of to TCDD-induced dysregulation of genes involved in regulation of food-intake. As the hypothalamus is the central nervous systems' regulatory center for food-intake and energy balance. Therefore, mRNA abundances in hypothalamic tissue from two rat strains with widely differing sensitivities to TCDD-induced wasting syndrome: TCDD-sensitive Long-Evans rats and TCDD-resistant Han/Wistar rats, 23h after exposure to TCDD (100μg/kg) or corn oil vehicle. TCDD exposure caused minimal transcriptional dysregulation in the hypothalamus, with only 6 genes significantly altered in Long-Evans rats and 15 genes in Han/Wistar rats. Two of the most dysregulated genes were Cyp1a1 and Nqo1, which are induced by TCDD across a wide range of tissues and are considered sensitive markers of TCDD exposure. The minimal response of the hypothalamic transcriptome to a lethal dose of TCDD at an early time-point suggests that the hypothalamus is not the predominant site of initial events leading to hypophagia and associated wasting. TCDD may affect feeding behaviour via events upstream or downstream of the hypothalamus, and further work is required to evaluate this at the level of individual hypothalamic nuclei and subregions.

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“…EcSOD loss is associated with a reduction in mean survival from 11.0 to 6.5 months in patients with pancreatic adenocarcinoma [135]. EcSOD over-expression inhibits in vitro cell proliferation, invasion, and clonogenic capacity of pancreatic cancer cells in a dose-dependent manner [135–137]. Furthermore, both transient and stable over-expression of EcSOD inhibited primary tumor growth and increased survival in tumor xenograft models [135–137].…”

Section: Expression Levels and Effects Of Ecsod In Cancersmentioning

confidence: 99%

“…EcSOD over-expression inhibits in vitro cell proliferation, invasion, and clonogenic capacity of pancreatic cancer cells in a dose-dependent manner [135–137]. Furthermore, both transient and stable over-expression of EcSOD inhibited primary tumor growth and increased survival in tumor xenograft models [135–137]. EcSOD was also found to decrease levels of VEGF and HIF-1α protein levels in pancreatic cancer cell lines [136 137].…”

Section: Expression Levels and Effects Of Ecsod In Cancersmentioning

confidence: 99%

“…Furthermore, both transient and stable over-expression of EcSOD inhibited primary tumor growth and increased survival in tumor xenograft models [135–137]. EcSOD was also found to decrease levels of VEGF and HIF-1α protein levels in pancreatic cancer cell lines [136 137]. Since HIF-1α and VEGF promote angiogenesis, EcSOD is likely inhibitory, restricting blood flow to the tumor.…”

Section: Expression Levels and Effects Of Ecsod In Cancersmentioning

confidence: 99%

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Extracellular superoxide dismutase and its role in cancer

Griess

Tom

Domann

et al. 2017

Free Radical Biology and Medicine

144

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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Extracellular superoxide dismutase suppresses hypoxia-inducible factor-1α in pancreatic cancer

Cited by 34 publications

References 34 publications

Efficacy and Biological Activity of Imatinib in Metastatic Dermatofibrosarcoma Protuberans (DFSP)

Efficacy and Biological Activity of Imatinib in Metastatic Dermatofibrosarcoma Protuberans (DFSP)

Transcriptional profiling of rat hypothalamus response to 2,3,7,8-tetrachlorodibenzo-ρ-dioxin

Extracellular superoxide dismutase and its role in cancer

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