Oncometabolites: Unconventional triggers of oncogenic signalling cascades

Sciacovelli, Marco; Frezza, Christian

doi:10.1016/j.freeradbiomed.2016.04.025

Cited by 150 publications

(132 citation statements)

References 94 publications

(131 reference statements)

Supporting

Mentioning

131

Contrasting

Unclassified

Order By: Relevance

“…disruption of the tricarboxylic acid (TCA) cycle, potentially associated with ROS, can give rise to accumulation of so-called oncometabolites such as succinate, which can reshape epigenetics by competitive inhibition of e.g. TET enzymes or histone demethylases[206, 207]. …”

Section: Epigenetic Silencing Of Duox In Cancermentioning

confidence: 99%

Paradoxical roles of dual oxidases in cancer biology

Little

Sulovari

Danyal

et al. 2017

Free Radical Biology and Medicine

View full text Add to dashboard Cite

Dysregulated oxidative metabolism is a well-recognized aspect of cancer biology, and many therapeutic strategies are based on targeting cancers by altering cellular redox pathways. The NADPH oxidases (NOXes) present an important enzymatic source of biological oxidants, and the expression and activation of several NOX isoforms are frequently dysregulated in many cancers. Cell-based studies have demonstrated a role for several NOX isozymes in controlling cell proliferation and/or cell migration, further supporting a potential contributing role for NOX in promoting cancer. While various NOX isoforms are often upregulated in cancers, paradoxical recent findings indicate that dual oxidases (DUOXes), normally prominently expressed in epithelial lineages, are frequently suppressed in epithelial-derived cancers by epigenetic mechanisms, although the functional relevance of such DUOX silencing has remained unclear. This review will briefly summarize our current understanding regarding the importance of reactive oxygen species (ROS) and NOXes in cancer biology, and focus on recent observations indicating the unique and seemingly opposing roles of DUOX enzymes in cancer biology. We will discuss current knowledge regarding the functional properties of DUOX, and recent studies highlighting mechanistic consequences of DUOX1 loss in lung cancer, and its consequences for tumor invasiveness and current anticancer therapy. Finally, we will also discuss potentially unique roles for the DUOX maturation factors. Overall, a better understanding of mechanisms that regulate DUOX and the functional consequences of DUOX silencing in cancer may offer valuable new diagnostic insights and novel therapeutic opportunities.

show abstract

Section: Epigenetic Silencing Of Duox In Cancermentioning

confidence: 99%

Paradoxical roles of dual oxidases in cancer biology

Little

Sulovari

Danyal

et al. 2017

Free Radical Biology and Medicine

View full text Add to dashboard Cite

show abstract

“…Mutations in the metabolic genes like fumarate hydratase, succinate dehydrogenase, and isocitrate dehydrogenase lead to the accumulation of fumarate, succinate, and D–2-hydroxyglutarate, respectively [3], which cause both metabolic and nonmetabolic dysregulation and potential transformation to malignancy.…”

Section: Introductionmentioning

confidence: 99%

Oncometabolite succinate promotes angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation

Zhao

et al. 2017

Oncotarget

View full text Add to dashboard Cite

Altered cellular metabolism is now generally acknowledged as a hallmark of cancer cells, the resultant abnormal oncometabolites cause both metabolic and nonmetabolic dysregulation and potential transformation to malignancy. A subset of cancers have been found to be associated with mutations in succinate dehydrogenase genes which result in the accumulation of succinate. However, the function of succinate in tumorigenesis remains unclear. In the present study, we aim to investigate the role of oncometabolite succinate in tumor angiogenesis. Our data demonstrated the accumulation of markedly elevated succinate in gastric cancer tissues compared with that in paracancerous tissues. Moreover, succinate was able to increase the chemotactic motility, tube-like structure formation and proliferation of primary human umbilical vascular endothelial cells (pHUVECs) in vitro, as well as promoting the blood vessel formation in transgenic zebrafish. Our mechanistic studies reveal that succinate upregulates vascular endothelial growth factor (VEGF) expression by activation of signal transducer and activator of transcription 3 (STAT3) and extracellular regulated kinase (ERK)1/2 via its receptor GPR91 in a HIF-1α independent mechanism. Taken together, these data indicate an important role of the succinate-GPR91 axis in tumor angiogenesis, which may enable development of a novel therapeutic strategy that targets cancer metabolism.

show abstract

“…Similarly, a mutation in SDH and FH would increase the cellular concentration of succinate and fumarate. These three metabolites succinate, fumarate and 2-HG are competitive inhibitors of 2-OG dependent dioxygenases like the TET enzymes and hence reduce global 5hmC levels in genomic DNA [33,34]. Notably, IDH mutations have frequently been reported in acute myeloid luekemia (AML), glioblastoma, melanoma and cancers of colon and lung [32].…”

Section: Interplay Between 5-hydroxymethylcytosine and Cancermentioning

confidence: 99%

Regulation and Functional Significance of 5-Hydroxymethylcytosine in Cancer

et al. 2017

View full text Add to dashboard Cite

Epigenetic modes of gene regulation are important for physiological conditions and its aberrant changes can lead to disease like cancer. 5-hydroxymethylcytosine (5hmC) is an oxidized form of 5-methylcytosine (5mC) catalyzed by Ten Eleven Translocation (TET) enzymes. 5hmC is considered to be a demethylation intermediate and is emerging as a stable and functional base modification. The global loss of 5hmC level is commonly observed in cancers and tumorigenic germline mutations in IDH, SDH and FH are found to be inhibiting TET activity. Although a global loss of 5hmC is characteristic in cancers, locus-specific 5hmC gain implicates selective gene expression control. The definitive role of 5hmC as a tumor suppressing or promoting modification can be deduced by identifying locus-specific 5hmC modification in different types of cancer. Determining the genes carrying 5hmC modifications and its selective variation will open up new therapeutic targets. This review outlines the role of global and locus-specific changes of 5hmC in cancers and the possible mechanisms underlying such changes. We have described major cellular factors that influence 5hmC levels and highlighted the significance of 5hmC in tumor micro environmental condition like hypoxia.

show abstract

Oncometabolites: Unconventional triggers of oncogenic signalling cascades

Cited by 150 publications

References 94 publications

Paradoxical roles of dual oxidases in cancer biology

Paradoxical roles of dual oxidases in cancer biology

Oncometabolite succinate promotes angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation

Regulation and Functional Significance of 5-Hydroxymethylcytosine in Cancer

Contact Info

Product

Resources

About