Elevated Levels Of Succinate Research Articles

The pathogenic role of succinate-SUCNR1: a critical function that induces renal fibrosis via M2 macrophage

BackgroundRenal fibrosis significantly contributes to the progressive loss of kidney function in chronic kidney disease (CKD), with alternatively activated M2 macrophages playing a crucial role in this progression. The serum succinate level is consistently elevated in individuals with diabetes and obesity, both of which are critical factors contributing to CKD. However, it remains unclear whether elevated succinate levels can mediate M2 polarization of macrophages and contribute to renal interstitial fibrosis.MethodsMale C57/BL6 mice were administered water supplemented with 4% succinate for 12 weeks to assess its impact on renal interstitial fibrosis. Additionally, the significance of macrophages was confirmed in vivo by using clodronate liposomes to deplete them. Furthermore, we employed RAW 264.7 and NRK-49F cells to investigate the underlying molecular mechanisms.ResultsSuccinate caused renal interstitial macrophage infiltration, activation of profibrotic M2 phenotype, upregulation of profibrotic factors, and interstitial fibrosis. Treatment of clodronate liposomes markedly depleted macrophages and prevented the succinate-induced increase in profibrotic factors and fibrosis. Mechanically, succinate promoted CTGF transcription via triggering SUCNR1-p-Akt/p-GSK3β/β-catenin signaling, which was inhibited by SUCNR1 siRNA. The knockdown of succinate receptor (SUCNR1) or pretreatment of anti-CTGF(connective tissue growth factor) antibody suppressed the stimulating effects of succinate on RAW 264.7 and NRK-49F cells.ConclusionsThe causative effects of succinate on renal interstitial fibrosis were mediated by the activation of profibrotic M2 macrophages. Succinate-SUCNR1 played a role in activating p-Akt/p-GSK3β/β-catenin, CTGF expression, and facilitating crosstalk between macrophages and fibroblasts. Our findings suggest a promising strategy to prevent the progression of metabolic CKD by promoting the excretion of succinate in urine and/or using selective antagonists for SUCNR1.

A novel SUCNR1 inhibitor alleviates dysbiosis through inhibition of host responses without direct interaction with host microbiota.

Type 2 diabetes (T2D) is a chronic metabolic disorder in which insulin resistance and impaired insulin secretion result in altered metabolite balance, specifically elevated levels of circulating glucose and succinate, which increases the risk of many pathologies, including periodontitis. Succinate, a tricarboxylic acid (TCA) cycle intermediate, can be produced and metabolized by both host cells and host microbiota, where elevated levels serve as an inflammation and pathogen threat signal through activating the succinate G protein-coupled receptor, SUCNR1. Modulating succinate-induced SUCNR1 signaling remains a promising therapeutic approach for pathologies resulting in elevated levels of succinate, such as T2D and periodontitis. Here, we demonstrate hyperglycemia and elevated intracellular succinate in a T2D mouse model and determine gut microbiome composition. Drawing on previous work demonstrating the ability of a novel SUCNR1 antagonist, compound 7a, to block inflammation and alleviate dysbiosis in a mouse model, we examined if compound 7a has an impact on the growth and virulence gene expression of bacterial and fungal human microbiota in vitro, and if 7a could reduce bone loss in a periodontitis-induced mouse model. T2D mice harbored a significantly different gut microbiome, suggesting the altered metabolite profile of T2D causes shifts in host-microbial community structure, with enrichment in succinate producers and consumers and mucin-degrading bacteria. Bacterial and fungal cultures showed that 7a did not influence growth or virulence gene expression, suggesting the therapeutic effects of 7a are a direct result of 7a interacting with host cells and that alterations in microbial community structure are driven by reduced host SUCNR1 signaling. This work further suggests that targeting SUCNR1 signaling is a promising therapeutic approach in metabolic, inflammatory, or immune disorders with elevated succinate levels.

Vinpocetine Ameliorates Metabolic-Syndrome-Associated Bladder Overactivity in Fructose-Fed Rats by Restoring Succinate-Modulated cAMP Levels and Exerting Anti-Inflammatory Effects in the Bladder Detrusor Muscle

Succinate and its receptor, the G protein-coupled receptor 91 (GPR91), have pathological implications in metabolic syndrome (MetS) and its associated bladder dysfunction, particularly in decreasing bladder cAMP levels and promoting proinflammation. Using fructose-fed rats (FFRs), a rat model of MetS, we investigate the effects of vinpocetine (a phosphodiesterase-1 inhibitor) and celecoxib (a selective cyclooxygenase-2 inhibitor) on MetS-associated bladder overactivity. Phenotypes of the overactive bladder, including increased micturition frequency and a shortened intercontractile interval in cystometry, were observed in FFRs, together with elevated succinate levels in the liver and serum and the downregulation of GPR91 in the liver and urinary bladder. Treatments with vinpocetine and celecoxib improved tissue fibrosis and ameliorated the overexpression of the inflammatory cytokines, such as IL-1β, in the liver and bladder. In bladder organ bath studies, vinpocetine, but not celecoxib, treatment restored the contraction and relaxation responses of the detrusor muscle strip in response to KCl, carbachol, and forskolin stimulation. At a molecular level, vinpocetine and celecoxib treatments modulated the downstream messengers of GPR91 (i.e., ERK1/2 and JNK), suppressed NF-κB and IL-1β expressions in the bladder, and prevented the fibrogenesis observed in FFRs. The exogenous application of succinate to a bladder organ bath significantly reduced the forskolin-induced cAMP production by the detrusor muscle, which was notably restored in the presence of vinpocetine. Together, these results suggest that vinpocetine may alleviate the MetS-associated bladder overactivity by restoring the succinate-modulated detrusor cAMP production and exerting the anti-inflammatory effects in the bladder detrusor muscle.

SDHA/B reduction promotes hepatocellular carcinoma by facilitating the deNEDDylation of cullin1 and stabilizing YAP/TAZ.

Succinate dehydrogenase enzyme (SDH) is frequently diminished in samples from patients with hepatocellular carcinoma (HCC), and SDH reduction is associated with elevated succinate level and poor prognosis in patients with HCC. However, the underlying mechanisms of how impaired SDH activity promotes HCC remain unclear. In this study, we observed remarkable downregulations of SDH subunits A and B (SDHA/B) in chronic liver injury-induced murine HCC models and patient samples. Subsequent RNA sequencing, hematoxylin and eosin staining, and immunohistochemistry analyses of HCC samples revealed that Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) were significantly upregulated in HCC, with their levels inversely correlating with that of SDHA/B. YAP/TAZ stability was greatly enhanced in SDHA/B-depleted HCC cells along with accumulation of succinate. Further mechanistic analyses demonstrated that impaired activity of SDHA/B resulted in succinate accumulation, which facilitated the deNEDDylation of cullin1 and therefore disrupted the E3 ubiquitin ligase SCF β-TrCP complex, consequently leading to YAP/TAZ stabilization and activation in HCC cells. The accelerated in vitro cell proliferation and in vivo tumor growth caused by SDHA/B reduction or succinate exposure were largely dependent on the aberrant activation of YAP/TAZ. Our study demonstrated that SDHA/B reduction promotes HCC proliferation by preventing the proteasomal degradation of YAP/TAZ through modulating cullin1 NEDDylation, thus binding SDH-deficient HCC cells to YAP/TAZ pathway and rendering these cells vulnerable to YAP/TAZ inhibition. Our findings warrant further investigation on the therapeutic effects of targeting YAP/TAZ in patients with HCC displaying reduced SDHA/B or elevated succinate levels.

P042 Succinate promotes the conversion from white to beige adipose tissue in Crohn’s Disease

Abstract Background Crohn’s disease (CD) is characterized by severe transmural inflammation with subsequent destruction of the intestinal barrier. Bacterial infiltration across this leaky gut facilitates access to the mesenteric fat and the development of a subsequent inflammatory reaction in the surrounding adipose tissue named creeping fat (CF). Dysbiosis in CD patients has been associated with an increase in succinate-producing bacteria and a decrease in succinate-consuming bacteria. In fact, elevated succinate levels have been found in the intestine and feces of CD patients. Furthermore, succinate is an inductor of beige adipogenesis in white adipose tissue progenitors. Methods Visceral and subcutaneous adipose tissue biopsies (VAT and SAT), serum, and plasma were obtained from a cohort of active CD (n=20), inactive CD (n=12), and control group (n=15). From adipose tissue biopsies, adipose-derived stem cells (ASCs) and adipose tissue macrophages (ATMs) were isolated. Different experiments were performed such as protein uncoupling protein 1 (UCP1)-immunohistochemistry and immunofluorescence, gene expression studies, adipose tissue explants, proteomic analysis of ASCs, succinate determinations, bio-impedancemetry, and infrared photographs. Results Succinate treatment increased markers of beige adipose tissue in ASCs from controls and inactive CD patients (Fig. A). Surprisingly, the markers of beige adipose tissue were already high in ASCs isolated from active CD, due to being exposed to an environment with high levels of succinate in vivo. Proteomic analysis of isolated CD-ASCs revealed that these cells secrete beige adipose tissue-related proteins compared to Control-ASCs (Fig. B). Furthermore, bacterial translocation increases the conversion of pre-adipocytes from white to beige adipose tissue in CD individuals (Fig. C). Immunohistochemical study of UCP-1, confirms increased staining in adipose samples from CD patients from both depots (SAT and VAT) (Fig. D). Altogether, adipose tissue depots from CD patients had a conversion from white to beige adipose tissue with a high protein UCP1-gene expression. Thermic images show an increase of temperature in the intestinal area of active CD patients that is not observed in inactive CD patients or the control group. Conclusion Understanding the role of beige adipose tissue in CD could help develop new therapeutic or diagnostic strategies in these patients.

Tricarboxylic acid cycle related-metabolites and risk of atrial fibrillation and heart failure

BackgroundTricarboxylic acid (TCA) cycle deregulation may predispose to cardiovascular diseases, but the role of TCA cycle-related metabolites in the development of atrial fibrillation (AF) and heart failure (HF) remains unexplored. This study sought to investigate the association of TCA cycle-related metabolites with risk of AF and HF. MethodsWe used two nested case-control studies within the PREDIMED study. During a mean follow-up for about 10 years, 512 AF and 334 HF incident cases matched by age (±5 years), sex and recruitment center to 616 controls and 433 controls, respectively, were included in this study. Baseline plasma levels of citrate, aconitate, isocitrate, succinate, malate and d/l-2-hydroxyglutarate were measured with liquid chromatography-tandem mass spectrometry. Multivariable conditional logistic regression models were fitted to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for metabolites and the risk of AF or HF. Potential confounders included smoking, family history of premature coronary heart disease, physical activity, alcohol intake, body mass index, intervention groups, dyslipidemia, hypertension, type 2 diabetes and medication use. ResultsComparing extreme quartiles of metabolites, elevated levels of succinate, malate, citrate and d/l-2-hydroxyglutarate were associated with a higher risk of AF [ORQ4 vs. Q1 (95% CI): 1.80 (1.21–2.67), 2.13 (1.45–3.13), 1.87 (1.25–2.81) and 1.95 (1.31–2.90), respectively]. One SD increase in aconitate was directly associated with AF risk [OR (95% CI): 1.16 (1.01–1.34)]. The corresponding ORs (95% CI) for HF comparing extreme quartiles of malate, aconitate, isocitrate and d/l-2-hydroxyglutarate were 2.15 (1.29–3.56), 2.16 (1.25–3.72), 2.63 (1.56–4.44) and 1.82 (1.10–3.04), respectively. These associations were confirmed in an internal validation, except for aconitate and AF. ConclusionThese findings underscore the potential role of the TCA cycle in the pathogenesis of cardiac outcomes.

The immunometabolite itaconate inhibits heme synthesis and remodels cellular metabolism in erythroid precursors

AbstractAs part of the inflammatory response by macrophages, Irg1 is induced, resulting in millimolar quantities of itaconate being produced. This immunometabolite remodels the macrophage metabolome and acts as an antimicrobial agent when excreted. Itaconate is not synthesized within the erythron but instead may be acquired from central macrophages within the erythroid island. Previously, we reported that itaconate inhibits hemoglobinization of developing erythroid cells. Herein we show that this action is accomplished by inhibition of tetrapyrrole synthesis. In differentiating erythroid precursors, cellular heme and protoporphyrin IX synthesis are reduced by itaconate at an early step in the pathway. In addition, itaconate causes global alterations in cellular metabolite pools, resulting in elevated levels of succinate, 2-hydroxyglutarate, pyruvate, glyoxylate, and intermediates of glycolytic shunts. Itaconate taken up by the developing erythron can be converted to itaconyl–coenzyme A (CoA) by the enzyme succinyl-CoA:glutarate-CoA transferase. Propionyl-CoA, propionyl-carnitine, methylmalonic acid, heptadecanoic acid, and nonanoic acid, as well as the aliphatic amino acids threonine, valine, methionine, and isoleucine, are increased, likely due to the impact of endogenous itaconyl-CoA synthesis. We further show that itaconyl-CoA is a competitive inhibitor of the erythroid-specific 5-aminolevulinate synthase (ALAS2), the first and rate-limiting step in heme synthesis. These findings strongly support our hypothesis that the inhibition of heme synthesis observed in chronic inflammation is mediated not only by iron limitation but also by limitation of tetrapyrrole synthesis at the point of ALAS2 catalysis by itaconate. Thus, we propose that macrophage-derived itaconate promotes anemia during an inflammatory response in the erythroid compartment.

P001 Succinate, a gut microbiota-derived metabolite, modulates the inflammatory status of the creeping fat in Crohn’s disease

Abstract Background Crohn’s disease [CD] is characterized by severe transmural inflammation with subsequent destruction of the intestinal barrier. Recent works suggest that bacterial infiltration across this leaky gut facilitates access to the mesenteric fat and the development of a subsequent inflammatory reaction in the surrounding adipose tissue named creeping fat [CF]. Dysbiosis in CD patients has been associated with an increase in succinate-producing bacteria and a decrease in succinate-consuming bacteria. In fact, elevated succinate levels have been found in the intestinal and faeces of CD patients. Succinate has been classically considered as a marker of hypoxia and tissue damage, assisting as a pro-inflammatory signal that triggers immune activation. However, recent observations support potential additional functions of succinate. We and others have shown that succinate plays a key role in fine-tuning of the inflammatory response, acting both as an alarmin and resolving molecule. Our hypothesis is that succinate, a microbiota-derived metabolite, is a new determinant of adipose tissue dysfunction in CD. Methods A well-characterized cohort was used to obtained mesenteric adipose tissue biopsies including a) 10 subjects with active CD that require surgery for their underlying pathology b) 10 subjects with inactive CD and c) 10 healthy controls undergoing surgery for non-acute process (herniorrhaphy, cholecystectomy for lithiasis, etc.). The groups were comparable in age, sex, and body mass index. We studied the effect of exogenous succinate in adipose tissue explants, adipose-stem cells (ASC), and adipose tissue macrophages (ATM) isolated from adipose tissue biopsies of CD patients with different clinical activity. Circulating succinate levels and inflammatory variables including hs-CRP and faecal calprotectin were also measured. Results We observed an increased expression of SUCNR1 in CF, including ASCs and ATMs, mainly in patients suffering from an active disease (figure 1A). Furthermore, succinate appears to elicit a different response in adipose tissue from CD patients, when activity status is considered. Thus, our results indicate that in an inflammatory local and systemic environment, such as occurs in CD active patients, succinate triggers a pro-inflammatory response in VAT depot, while when subjects are in a remission period, the response of VAT explants to succinate is similar to than the observed in healthy subjects, promoting an anti-inflammatory expression profile (Figure 1B). Interestingly, we found elevated circulating succinate levels in active CD patients but those decrease drastically in patients in remission of the disease (Figure 1C). Conclusion Succinate has a relevant role in adipose tissue dysfunction in CD.

Targeting alveolar-specific succinate dehydrogenase A attenuates pulmonary inflammation during acute lung injury.

Acute lung injury (ALI) is an inflammatory lung disease, which manifests itself in patients as acute respiratory distress syndrome (ARDS). Previous studies have implicated alveolar‐epithelial succinate in ALI protection. Therefore, we hypothesized that targeting alveolar succinate dehydrogenase SDH A would result in elevated succinate levels and concomitant lung protection. Wild‐type (WT) mice or transgenic mice with targeted alveolar‐epithelial Sdha or hypoxia‐inducible transcription factor Hif1a deletion were exposed to ALI induced by mechanical ventilation. Succinate metabolism was assessed in alveolar‐epithelial via mass spectrometry as well as redox measurements and evaluation of lung injury. In WT mice, ALI induced by mechanical ventilation decreased SDHA activity and increased succinate in alveolar‐epithelial. In vitro, cell‐permeable succinate decreased epithelial inflammation during stretch injury. Mice with inducible alveolar‐epithelial Sdha deletion (Sdhaloxp/loxp SPC‐CreER mice) revealed reduced lung inflammation, improved alveolar barrier function, and attenuated histologic injury. Consistent with a functional role of succinate to stabilize HIF, Sdhaloxp/loxp SPC‐CreER experienced enhanced Hif1a levels during hypoxia or ALI. Conversely, Hif1aloxp/loxp SPC‐CreER showed increased inflammation with ALI induced by mechanical ventilation. Finally, wild‐type mice treated with intra‐tracheal dimethlysuccinate were protected during ALI. These data suggest that targeting alveolar‐epithelial SDHA dampens ALI via succinate‐mediated stabilization of HIF1A. Translational extensions of our studies implicate succinate treatment in attenuating alveolar inflammation in patients suffering from ARDS.

The Role of Succinate in the Regulation of Intestinal Inflammation.

Succinate is a metabolic intermediate of the tricarboxylic acid (TCA) cycle within host cells. Succinate is also produced in large amounts during bacterial fermentation of dietary fiber. Elevated succinate levels within the gut lumen have been reported in association with microbiome disturbances (dysbiosis), as well as in patients with inflammatory bowel disease (IBD) and animal models of intestinal inflammation. Recent studies indicate that succinate can activate immune cells via its specific surface receptor, succinate receptor 1(SUCNR1), and enhance inflammation. However, the role of succinate in inflammatory processes within the gut mucosal immune system is unclear. This review includes current literature on the association of succinate with intestinal inflammation and the potential role of succinate–SUCNR1 signaling in gut immune functions.

Catalytic Coupling of Oxidative Phosphorylation, ATP Demand, and Reactive Oxygen Species Generation

Competing models of mitochondrial energy metabolism in the heart are highly disputed. In addition, the mechanisms of reactive oxygen species (ROS) production and scavenging are not well understood. To deepen our understanding of these processes, a computer model was developed to integrate the biophysical processes of oxidative phosphorylation and ROS generation. The model was calibrated with experimental data obtained from isolated rat heart mitochondria subjected to physiological conditions and workloads. Model simulations show that changes in the quinone pool redox state are responsible for the apparent inorganic phosphate activation of complex III. Model simulations predict that complex III is responsible for more ROS production during physiological working conditions relative to complex I. However, this relationship is reversed under pathological conditions. Finally, model analysis reveals how a highly reduced quinone pool caused by elevated levels of succinate is likely responsible for the burst of ROS seen during reperfusion after ischemia.

Abstract A04: Metabolic reprogramming of MYCN amplified neuroblastoma

Abstract Neuroblastoma (NB) is a highly malignant embryonic tumor of neural crest origin and accounts for 15% of all cancer deaths in children. Amplification of the MYCN oncogene, which occurs in ~25% of patients, is the most reliable marker of metastatic disease and predicts poor outcome. Recent findings show MYCN reprograms NB cell metabolism to promote glycolysis and shunting of glutamate into the TCA cycle, causing dependence on increased levels of TCA intermediates, such as a-KG and succinate. Allelic loss of the short arm of chromosome 1, (1p36) is associated with the vast majority of MYCN amplified NB, and a candidate tumor suppressor gene (TSG) in this region is succinate dehydrogenase subunit B,SDHB, which encodes a core component of the succinate dehydrogenase (SDH) complex, converting succinate to fumarate. We show that MYCN-amplified NB cells, with 1p deletion, have reduced SDHB protein levels and elevated succinate levels. Thus, we are now testing a model that the combined loss of SDH activity with MYCN amplification causes dramatic accumulation of cytosolic succinate, which in turn stabilizes HIF1α to accelerate NB pathogenesis in vivo. To test this model, we have generated mutations in zebrafish sdhb to determine if 1) it is normally required for sympathetic neuron differentiation and 2) cooperates with MYCN to accelerate zebrafish NB in vivo (Zhu et. al, Cancer Cell, 2012). As HIF1a is predicted to be upregulated in SDH-deficient cells, as well as MYCN-amplified NB, we have also generated stable HIF1α transgenic zebrafish lines to directly determine if HIF1α alone is sufficient to drive NB or cooperates with MYCN to accelerate it. The results from our studies of sdhb loss and hif1α gain on peripheral sympathetic nervous system development and NB formation in vivo will be discussed as well as potential therapeutic approaches to target SDH/MYCN-dependent tumors. Citation Format: Monique Morrison, Scott Khuu, Joshua Schiffman, Bradley Cairns, Jared Rutter, Dennis Winge, Frank Speleman, Rodney Stewart. Metabolic reprogramming of MYCN amplified neuroblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A04.

Succinate causes α-SMA production through GPR91 activation in hepatic stellate cells

Succinate acts as an extracellular signaling molecule as well as an intermediate in the citric acid cycle. It binds to and activates its specific G protein-coupled receptor 91 (GPR91). GPR91 is present in hepatic stellate cells (HSCs), but its role in hepatic fibrogenesis remains unclear. Cultured HSCs treated with succinate showed increased protein expression of GPR91 and α-smooth muscle actin (α-SMA), markers of fibrogenic response. Succinate also increased mRNA expression of α-SMA, transforming growth factor β (TGF-β), and collagen type I. Transfection of siRNA against GPR91 abrogated succinate-induced increases in α-SMA expression. Malonate, an inhibitor of succinate dehydrogenase (SDH), increased succinate levels in cultured HSCs and increased GPR91 and α-SMA expression. Feeding mice a methionine- and choline-deficient (MCD) diet is a widely used technique to create an animal model of nonalcoholic steatohepatitis (NASH). HSCs cultured in MCD media showed significantly decreased SDH activity and increased succinate concentration and GPR91 and α-SMA expression. Similarly, palmitate treatment significantly decreased SDH activity and increased GPR91 and α-SMA expression. Finally, C57BL6/J mice fed the MCD diet had elevated succinate levels in their plasma. The MCD diet also decreased SDH activity, increased succinate concentration, and increased GPR91 and α-SMA expression in isolated HSCs. Collectively, our results show that succinate plays an important role in HSC activation through GPR91 induction, and suggest that succinate and GPR91 may represent new therapeutic targets for modulating hepatic fibrosis.

Abstract 1088: HOXB13 inhibition of succinate dehydrogenase leads to epithelial-to-mesenchymal transition in mouse ovarian cancer cell lines.

Abstract HOXB13 is a homeobox gene whose dysregulation has been implicated in cancer. We have previously shown that HOXB13 plays an oncogenic role in ovarian cancer by driving epithelial-to-mesenchymal transition (EMT); however the mechanism by which this occurs has not been established. Global metabolomics profiling revealed that overexpression of HOXB13 in genetically defined mouse ovarian cancer cell lines inhibits succinate dehydrogenase (SDH) activity. Targeted-knockdown of the SDH subunit SdhB by shRNA results in mislocalization of E-cadherin and a spindle-shaped morphology suggestive of EMT. Metabolomics and real-time flux analysis showed that knockdown of SdhB results in elevated levels of succinate as well as defective mitochondrial respiration. Despite the mitochondrial respiration defect, SdhB knockdown cells display increased anchorage-independent growth in soft agar and enhanced xenograft tumor formation. Elevated levels of succinate have been shown to inhibit α-ketoglutarate requiring enzymes such as the Jumanji C (JmjC)-domain containing H3K27 demethylases, UTX and JMJD3. Indeed, knockdown of SdhB results in a hypermethylated epigenome as evidenced by increased levels of H3K27me2 and H3K27me3. Both the epigenetic and EMT phenotypes can be recapitulated by pharmacological inhibition of UTX and JMJD3 in control cells. These data point to a mechanism wherein modulation of oncometabolite levels can affect the epigenome, thereby influencing cancer cell morphology and tumorigenic properties. Citation Format: Paul-Joseph Aspuria, Dong-Joo Cheon, Maricel Gozo, Brenda Salumbides, Laurent Vergnes, John Asara, Karen Reue, Elizabeth Kensicki, Beth Karlan, Sandra Orsulic. HOXB13 inhibition of succinate dehydrogenase leads to epithelial-to-mesenchymal transition in mouse ovarian cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1088. doi:10.1158/1538-7445.AM2013-1088