Regulation of succinate dehydrogenase and role of succinate in cancer

Pozza, Elisa Dalla; Dando, Ilaria; Pacchiana, Raffaella; Liboi, Elio; Scupoli, Maria Teresa; Donadelli, Massimo; Palmieri, Marta

doi:10.1016/j.semcdb.2019.04.013

Cited by 142 publications

(111 citation statements)

References 138 publications

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“…Recent evidence showed that succinate and fumarate accumulation contribute to SNAIL-, TWIST- and ZEB-mediated EMT via the inhibition of DNA and/or histone demethylases. In PCC, PGL and ovarian cancers, SDHB mutation or knockdown led to histone methylation and increased expression of EMT markers LOXL2, TWIST1/2, TCF3, and metalloproteases (MMPs) [ 13 – 15 ]. In CRC cells, SDHB knockdown also activated TGF-β signaling and SNAIL-dependent EMT [ 16 ].…”

Section: Effects Of Metabolic Rewiring On Metastatic Signaling Cascadmentioning

confidence: 99%

“…The second mechanism involved activation of the Succinate Receptor 1 (SUNCR1), a G-protein coupled receptor for succinate. Upon binding to succinate, SUNCR1 up-regulates VEGF by activating ERK1/2 and STAT3 signaling in a HIF1α-independent manner [ 13 ]. Accordingly, succinate may exert a pro- or anti-angiogenic effect and tumor metastasis depending on the cellular context of succinate accumulation.…”

Section: Effects Of Metabolic Rewiring On Metastatic Signaling Cascadmentioning

confidence: 99%

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Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications

et al. 2020

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Tumor metastasis is the major cause of mortality from cancer. Metabolic rewiring and the metastatic cascade are highly intertwined, co-operating to promote multiple steps of cancer metastasis. Metabolites generated by cancer cells influence the metastatic cascade, encompassing epithelial-mesenchymal transition (EMT), survival of cancer cells in circulation, and metastatic colonization at distant sites. A variety of molecular mechanisms underlie the prometastatic effect of tumor-derived metabolites, such as epigenetic deregulation, induction of matrix metalloproteinases (MMPs), promotion of cancer stemness, and alleviation of oxidative stress. Conversely, metastatic signaling regulates expression and activity of rate-limiting metabolic enzymes to generate prometastatic metabolites thereby reinforcing the metastasis cascade. Understanding the complex interplay between metabolism and metastasis could unravel novel molecular targets, whose intervention could lead to improvements in the treatment of cancer. In this review, we summarized the recent discoveries involving metabolism and tumor metastasis, and emphasized the promising molecular targets, with an update on the development of small molecule or biologic inhibitors against these aberrant situations in cancer.

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Section: Effects Of Metabolic Rewiring On Metastatic Signaling Cascadmentioning

confidence: 99%

Section: Effects Of Metabolic Rewiring On Metastatic Signaling Cascadmentioning

confidence: 99%

Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications

et al. 2020

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“…Complex II mutations, principally affecting SDHB and SDHD subunits, have been associated with various cancers including hereditary paraganglioma and pheochromocytoma (i.e., neuroendocrine tumors of the paraganglionic tissue), gastrointestinal stromal tumors [ 60 ], and renal cell carcinoma [ 61 ]. Therefore, SDH has now been defined as a tumor suppressor and succinate as an oncometabolite [ 62 , 63 ].…”

Section: Effects Of Mutations In the Subunits Of Complexes I And Imentioning

confidence: 99%

Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

Nakhle

Rodriguez

Vignais

2020

IJMS

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Mitochondria are essential cellular components that ensure physiological metabolic functions. They provide energy in the form of adenosine triphosphate (ATP) through the electron transport chain (ETC). They also constitute a metabolic hub in which metabolites are used and processed, notably through the tricarboxylic acid (TCA) cycle. These newly generated metabolites have the capacity to feed other cellular metabolic pathways; modify cellular functions; and, ultimately, generate specific phenotypes. Mitochondria also provide intracellular signaling cues through reactive oxygen species (ROS) production. As expected with such a central cellular role, mitochondrial dysfunctions have been linked to many different diseases. The origins of some of these diseases could be pinpointed to specific mutations in both mitochondrial- and nuclear-encoded genes. In addition to their impressive intracellular tasks, mitochondria also provide intercellular signaling as they can be exchanged between cells, with resulting effects ranging from repair of damaged cells to strengthened progression and chemo-resistance of cancer cells. Several therapeutic options can now be envisioned to rescue mitochondria-defective cells. They include gene therapy for both mitochondrial and nuclear defective genes. Transferring exogenous mitochondria to target cells is also a whole new area of investigation. Finally, supplementing targeted metabolites, possibly through microbiota transplantation, appears as another therapeutic approach full of promises.

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“…As a consequence, the relative concentrations of these metabolites are critical for histone and DNA methylation in the nucleus, and thus gene expression, as well as the regulation of HIF-1α levels. A compromise in SDH or FH activities leads to the accumulation of succinate or fumarate, respectively, causing the inhibition of DNA and histone demethylation [68,69]. Inactivating mutations in SDH are associated with pheochromocytomas and paragangliomas, sporadic renal cancer and gastrointestinal stromal tumors [69].…”

Section: Metabolism and The Epigenetic Control Of Epithelial-mesenmentioning

confidence: 99%

“…A compromise in SDH or FH activities leads to the accumulation of succinate or fumarate, respectively, causing the inhibition of DNA and histone demethylation [68,69]. Inactivating mutations in SDH are associated with pheochromocytomas and paragangliomas, sporadic renal cancer and gastrointestinal stromal tumors [69]. Accumulation of succinate causes epigenetic silencing of miR-200 and eventually EMT [70].…”

Section: Metabolism and The Epigenetic Control Of Epithelial-mesenmentioning

confidence: 99%

Metabolic Plasticity and Epithelial-Mesenchymal Transition

Thomson

Balcells

Cascante

2019

JCM

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A major transcriptional and phenotypic reprogramming event during development is the establishment of the mesodermal layer from the ectoderm through epithelial-mesenchymal transition (EMT). EMT is employed in subsequent developmental events, and also in many physiological and pathological processes, such as the dissemination of cancer cells through metastasis, as a reversible transition between epithelial and mesenchymal states. The remarkable phenotypic remodeling accompanying these transitions is driven by characteristic transcription factors whose activities and/or activation depend upon signaling cues and co-factors, including intermediary metabolites. In this review, we summarize salient metabolic features that enable or instigate these transitions, as well as adaptations undergone by cells to meet the metabolic requirements of their new states, with an emphasis on the roles played by the metabolic regulation of epigenetic modifications, notably methylation and acetylation.

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Regulation of succinate dehydrogenase and role of succinate in cancer

Cited by 142 publications

References 138 publications

Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications

Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications

Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer

Metabolic Plasticity and Epithelial-Mesenchymal Transition

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