fumarates and Carcinogenesis

Pheochromocytomas and paragangliomas (PPGLs) with SDHx pathogenic variants (PVs) are characterized by a higher intratissular succinate/fumarate ratio (RS/F) than non-SDHx-mutated ones. Also, an increase in serum succinate levels has been reported in patients with germline SDHB or SDHD PV.. To assess whether measurement of serum succinate, fumarate levels, and RS/F might aid identification of an SDHx germline PV/likely pathogenic variant (LPV) in patients with PPGL or in asymptomatic relatives; and to guide identification of a PV/LPV among the variants of unknown significance (VUS) identified in SDHx by next-generation sequencing.. This prospective monocentric study included 93 patients attending an endocrine oncogenetic unit for genetic testing. Succinate and fumarate were measured in serum by gas chromatography coupled to mass spectrometry. The RS/F was calculated to assess SDH enzymatic function. Diagnostic performance was assessed by receiver operating characteristic analysis.. RS/F had a higher discriminant power than succinate alone to identify an SDHx PV/LPV in patients with PPGL. However, SDHD PVs/LPVs are frequently missed. Only RS/F differed between asymptomatic SDHB/SDHD PV/LPV carriers and SDHB/SDHD-linked patients with PPGL. Finally RS/F could be helpful to easily evaluate the functional impact of VUS in SDHx.. Measurement of serum RS/F in patients with PPGL and in asymptomatic relatives is a valuable initial workup tool to detect those carrying a germline PV/LPV in SDHx. Its discriminative power is equal or superior to those of succinate measured alone. SDHD PVs/LPVs are less frequently identified by these biochemical tools. Use of RS/F for SDHx VUS reclassification needs to be evaluated further.

Topics: Adrenal Gland Neoplasms; Carcinogenesis; Cell Transformation, Neoplastic; Fumarates; Germ-Line Mutation; Humans; Paraganglioma; Pheochromocytoma; Prospective Studies; Succinate Dehydrogenase; Succinic Acid

Fumarate is an oncometabolite. However, the mechanism underlying fumarate-exerted tumorigenesis remains unclear. Here, utilizing human type2 papillary renal cell carcinoma (PRCC2) as a model, we show that fumarate accumulates in cells deficient in fumarate hydratase (FH) and inhibits PTEN to activate PI3K/AKT signaling. Mechanistically, fumarate directly reacts with PTEN at cysteine 211 (C211) to form S-(2-succino)-cysteine. Succinated C211 occludes tethering of PTEN with the cellular membrane, thereby diminishing its inhibitory effect on the PI3K/AKT pathway. Functionally, re-expressing wild-type FH or PTEN C211S phenocopies an AKT inhibitor in suppressing tumor growth and sensitizing PRCC2 to sunitinib. Analysis of clinical specimens indicates that PTEN C211 succination levels are positively correlated with AKT activation in PRCC2. Collectively, these findings elucidate a non-metabolic, oncogenic role of fumarate in PRCC2 via direct post-translational modification of PTEN and further reveal potential stratification strategies for patients with FH loss by combinatorial AKTi and sunitinib therapy.

Topics: Carcinogenesis; Carcinoma, Papillary; Carcinoma, Renal Cell; Cysteine; Drug Resistance, Neoplasm; Fumarate Hydratase; Fumarates; Humans; Kidney Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Sunitinib

EBV infection is a recognized epigenetic driver of carcinogenesis. We previously showed that EBV could protect cancer cells from TNF-induced necroptosis. This study aims to explore the epigenetic mechanisms allowing cancer cells with EBV infection to escape from RIP3-dependent necroptosis.

Topics: Aged; Animals; Carcinogenesis; Carcinoma; Cell Line, Tumor; Cellular Reprogramming; DNA Methylation; Epithelial Cells; Female; Fumarates; Gene Expression Regulation, Neoplastic; Herpesvirus 4, Human; Heterografts; Host-Pathogen Interactions; Humans; Ketoglutaric Acids; Male; Mice; Middle Aged; Nasopharyngeal Neoplasms; Nasopharynx; Necroptosis; Promoter Regions, Genetic; Receptor-Interacting Protein Serine-Threonine Kinases; Signal Transduction; Survival Analysis; Viral Matrix Proteins

Topics: Carcinogenesis; Cell Proliferation; Cobalt; Female; Ferric Compounds; Fumarates; HeLa Cells; Humans; Keratinocytes; Metabolomics; Nanoparticles; Neoplasms; Uterine Cervical Neoplasms

How mitochondrial glutaminolysis contributes to redox homeostasis in cancer cells remains unclear. Here we report that the mitochondrial enzyme glutamate dehydrogenase 1 (GDH1) is commonly upregulated in human cancers. GDH1 is important for redox homeostasis in cancer cells by controlling the intracellular levels of its product alpha-ketoglutarate and subsequent metabolite fumarate. Mechanistically, fumarate binds to and activates a reactive oxygen species scavenging enzyme glutathione peroxidase 1. Targeting GDH1 by shRNA or a small molecule inhibitor R162 resulted in imbalanced redox homeostasis, leading to attenuated cancer cell proliferation and tumor growth.

Topics: Antioxidants; Carcinogenesis; Fumarates; Gene Expression Regulation, Neoplastic; Glutamate Dehydrogenase; Glutathione; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Humans; Ketoglutaric Acids; Leukemia; Mitochondria; Oxidation-Reduction; Primary Cell Culture; Reactive Oxygen Species; Signal Transduction