Revisiting the TCA cycle: signaling to tumor formation

Raimundo, Nuno; Baysal, Bora E.; Shadel, Gerald S.

doi:10.1016/j.molmed.2011.06.001

Cited by 217 publications

(186 citation statements)

References 67 publications

Supporting

Mentioning

184

Contrasting

Unclassified

Order By: Relevance

“…Although the source of 2-HG is not fully understood, experimental evidences indicate that IDH1 and IDH2 have a role in the production of d-2-HG (Matsunaga et al, 2012). d-2-HG and its enantiomer l-2-HG are linked to the Krebs cycle (Raimundo et al, 2011) and are found to be elevated in certain types of cancer (Dang et al, 2009;Rakheja et al, 2011) and in different variants of the neurometabolic 2-hydroxyglutaric aciduria. In relation to the latter defect, a recent study from Nota et al (2013) reported 12 recessive mutations (Ser193Trp, Arg282Gly, Arg282Cys, Gly167Arg, Pro45Leu, Glu144Gln, Met202Thr, Tyr297Cys, Tyr256*, Ala9Profs*82, A274Ilefs*24, and Arg173Glyfs*2) found in the CIC gene of three individuals and their families that cause combined d-2-and l-2-hydroxyglutaric aciduria.…”

Section: Citrate In Neurodevelopmental Syndromes and Hydroxyglutaricmentioning

confidence: 99%

Citrate – new functions for an old metabolite

Iacobazzi

Infantino

2014

Biological Chemistry

226

187

View full text Add to dashboard Cite

Abstract:Citrate is an important substrate in cellular energy metabolism. It is produced in the mitochondria and used in the Krebs cycle or released into cytoplasm through a specific mitochondrial carrier, CIC. In the cytosol, citrate and its derivatives, acetyl-CoA and oxaloacetate, are used in normal and pathological processes. Beyond the classical role as metabolic regulator, recent studies have highlighted that citrate is involved in inflammation, cancer, insulin secretion, histone acetylation, neurological disorders, and non-alcoholic fatty liver disease. Monitoring changes in the citrate levels could therefore potentially be used as diagnostic tool. This review highlights these new aspects of citrate functions.

show abstract

Section: Citrate In Neurodevelopmental Syndromes and Hydroxyglutaricmentioning

confidence: 99%

Citrate – new functions for an old metabolite

Iacobazzi

Infantino

2014

Biological Chemistry

226

187

View full text Add to dashboard Cite

show abstract

“…[12][13][14] The currently known mechanisms underlying tumorigenesis linked to defects in the TCA cycle are well reviewed. 15,16 Defects in the SDH, FH, and IDH genes inhibit prolyl hydroxylases, leading to decreased hydroxylation of hypoxia-inducible factor-α. This results in activation of the hypoxia pathway, which supports tumor formation by activating angiogenesis, glucose metabolism, cell motility, and cell survival.…”

Section: © American College Of Medical Genetics and Genomicsmentioning

confidence: 99%

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

Evenepoel

Papathomas

Krol

et al. 2015

Genetics in Medicine

View full text Add to dashboard Cite

The tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) is a heterotetramer protein complex consisting of four subunits encoded by nuclear genes. These include SDHA and SDHB, which form the catalytic domain, and SDHC and SDHD, which anchor the complex to the inner mitochondrial membrane. 1 The assembly factors, SDHAF1 and SDHAF2, ensure both structural and functional integrity of the complex. 2,3 SDH, also called mitochondrial complex II, is the only enzyme involved in both the electron transport chain and the TCA cycle, where it catalyzes the oxidation of succinate to fumarate. 1 The TCA cycle is central to the metabolism of sugars, lipids, and amino acids and is a major source of adenosine triphosphate in cells. In addition, the cycle also seems to be involved in tumorigenesis; enzymes of the TCA cycle are involved in the pathogenesis of several tumor types. SDH mutations have been involved in the etiopathogeny of pheochromocytomas (PCCs), paragangliomas (PGLs), gastrointestinal stromal tumors (GISTs), renal-cell carcinomas (RCCs), and pituitary adenomas (PAs). 1,2,[4][5][6][7][8][9] In addition, mutations in fumarate hydratase (FH), another member of the TCA cycle and which catalyzes the hydration of fumarate to malate, predispose to tumor formation, including RCCs, cutaneous and uterine leiomyomas, and PCCs/PGLs. 10,11 Finally, isocitrate dehydrogenase (IDH), which catalyzes the oxidative decarboxylation of isocitrate, is frequently mutated in specific types of cartilaginous tumors, hematological malignancies, and gliomas. 12-14 The currently known mechanisms underlying tumorigenesis linked to defects in the TCA cycle are well reviewed. 15,16 Defects in the SDH, FH, and IDH genes inhibit prolyl hydroxylases, leading to decreased hydroxylation of hypoxia-inducible factor-α. This results in activation of the hypoxia pathway, which supports tumor formation by activating angiogenesis, glucose metabolism, cell motility, and cell survival. Furthermore, defects in these enzymes lead to epigenetic alterations through an accumulation of oncometabolites inhibiting α-ketoglutarate-dependent dioxygenases, which are involved in DNA and histone demethylation. In addition to SDH-associated tumorigenesis, constitutional complex II deficiencies caused by SDHA, SDHB, SDHD, and SDHAF1 mutations may also lead to Leigh syndrome, infantile leukodystrophies, and cardiomyopathy. 3,[17][18][19] In the current review, our aim is to report all currently known SDH mutations and define their nature and spectrum in SDHrelated tumors, including PCCs/PGLs, GISTs, RCCs, and PAs, as well as in other unusual tumors arising in SDH mutation carriers. We performed bioinformatics analysis using SIFT, Polyphen2, and Mutation Assessor and compared the results with those of SDHA/SDHB immunohistochemistry (IHC) to predict the functional impact of nonsynonymous mutations. Finally, we explored and report here the nature of the second hit in all tumors arising in the SDH deficiency setting. The tricarboxylic acid, or Krebs, cycle is cent...

show abstract

“…28,29 High oxygen consumption through mitochondrial respiration was observed in shCont cells. Nonetheless, reduction of PP2A Cα led to suppressed mitochondrial respiratory capacity at the basal and maximal level.…”

Section: Discussionmentioning

confidence: 99%

Protein phosphatase 2A Cα regulates proliferation, migration, and metastasis of osteosarcoma cells

Yang

Okamura

Morimoto

et al. 2016

Laboratory Investigation

View full text Add to dashboard Cite

Osteosarcoma is the most frequent primary bone tumor. Serine/threonine protein phosphatase 2A (PP2A) participates in regulating many important physiological processes, such as cell cycle, growth, apoptosis, and signal transduction. In this study, we examined the expression and function of PP2A Cα in osteosarcoma cells. PP2A Cα expression was expected to be higher in malignant osteosarcoma tissues. PP2A Cα expression level and PP2A activity was higher in malignant osteosarcoma LM8 cells compared with that in primary osteoblasts and in the osteoblast-like cell line MC3T3-E1. Okadaic acid, an inhibitor of PP2A, reduced cell viability and induced apoptosis in LM8 cells. PP2A Cα-knockdown LM8 cells (shPP2A) exhibited less striking filopodial and lamellipodial structures than that in original LM8 cells. Focal adhesion kinase phosphorylation and NF-κB activity decreased in shPP2A-treated cells. Sensitivity to serum deprivation-induced apoptosis increased in shPP2A-treated cells, accompanied by a lower expression level of anti-apoptotic BCL-2 in these cells. Reduction of PP2A Cα resulted in a decrease in the migration ability of LM8 cells in vitro. Reduction in PP2A Cα levels in vivo suppressed proliferation and metastasis in LM8 cells. PP2A Cα expression was also higher in human osteosarcoma MG63 and SaOS-2 cells than that in primary osteoblasts and MC3T3-E1 cells, and reduction in PP2A Cα levels suppressed the cell proliferation rate and migration ability of MG63 cells. These results indicate that PP2A Cα has a critical role in the proliferation and metastasis of osteosarcoma cells; therefore, its inhibition could potentially suppress the malignancy of osteosarcoma cells.

show abstract

Revisiting the TCA cycle: signaling to tumor formation

Cited by 217 publications

References 67 publications

Citrate – new functions for an old metabolite

Citrate – new functions for an old metabolite

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

Protein phosphatase 2A Cα regulates proliferation, migration, and metastasis of osteosarcoma cells

Contact Info

Product

Resources

About