Tumor Glucose Metabolism Research Articles

Non-proteolytic ubiquitination of Hexokinase 2 by HectH9 controls tumor metabolism and cancer stem cell expansion

Enormous efforts have been made to target metabolic dependencies of cancer cells for developing new therapies. However, the therapeutic efficacy of glycolysis inhibitors is limited due to their inability to elicit cell death. Hexokinase 2 (HK2), via its mitochondrial localization, functions as a central nexus integrating glycolysis activation and apoptosis resilience. Here we identify that K63-linked ubiquitination by HectH9 regulates the mitochondrial localization and function of HK2. Through stable isotope tracer approach and functional metabolic analyses, we show that HectH9 deficiency impedes tumor glucose metabolism and growth by HK2 inhibition. The HectH9/HK2 pathway regulates cancer stem cell (CSC) expansion and CSC-associated chemoresistance. Histological analyses show that HectH9 expression is upregulated and correlated with disease progression in prostate cancer. This work uncovers that HectH9 is a novel regulator of HK2 and cancer metabolism. Targeting HectH9 represents an effective strategy to achieve long-term tumor remission by concomitantly disrupting glycolysis and inducing apoptosis.

Bitter melon juice-intake modulates glucose metabolism and lactate efflux in tumors in its efficacy against pancreatic cancer.

The established role of bitter melon juice (BMJ), a natural product, in activating master metabolic regulator adenosine monophosphate-activated protein kinase in pancreatic cancer (PanC) cells served as a basis for pursuing deeper investigation into the underlying metabolic alterations leading to BMJ efficacy in PanC. We investigated the comparative metabolic profiles of PanC cells with differential KRAS mutational status on BMJ exposure. Specifically, we employed nuclear magnetic resonance (NMR) metabolomics and in vivo imaging platforms to understand the relevance of altered metabolism in PanC management by BMJ. Multinuclear NMR metabolomics was performed, as a function of time, post-BMJ treatment followed by partial least square discriminant analysis assessments on the quantitative metabolic data sets to visualize the treatment group clustering; altered glucose uptake, lactate export and energy state were identified as the key components responsible for cell death induction. We next employed PANC1 xenograft model for assessing in vivo BMJ efficacy against PanC. Positron emission tomography ([18FDG]-PET) and magnetic resonance imaging on PANC1 tumor-bearing animals reiterated the in vitro results, with BMJ-associated significant changes in tumor volumes, tumor cellularity and glucose uptake. Additional studies in BMJ-treated PanC cells and xenografts displayed a strong decrease in the expression of glucose and lactate transporters GLUT1 and MCT4, respectively, supporting their role in metabolic changes by BMJ. Collectively, these results highlight BMJ-induced modification in PanC metabolomics phenotype and establish primarily lactate efflux and glucose metabolism, specifically GLUT1 and MCT4 transporters, as the potential metabolic targets underlying BMJ efficacy in PanC.

Long Noncoding RNA MALAT1 Regulates Cancer Glucose Metabolism by Enhancing mTOR-Mediated Translation of TCF7L2.

Reprogrammed glucose metabolism of enhanced aerobic glycolysis (or the Warburg effect) is known as a hallmark of cancer. The roles of long noncoding RNAs (lncRNA) in regulating cancer metabolism at the level of both glycolysis and gluconeogenesis are mostly unknown. We previously showed that lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) acts as a proto-oncogene in hepatocellular carcinoma (HCC). Here, we investigated the role of MALAT1 in regulating cancer glucose metabolism. MALAT1 upregulated the expression of glycolytic genes and downregulated gluconeogenic enzymes by enhancing the translation of the metabolic transcription factor TCF7L2. MALAT1-enhanced TCF7L2 translation was mediated by upregulation of SRSF1 and activation of the mTORC1-4EBP1 axis. Pharmacological or genetic inhibition of mTOR and Raptor or expression of a hypophosphorylated mutant version of eIF4E-binding protein (4EBP1) resulted in decreased expression of TCF7L2. MALAT1 expression regulated TCF7L2 mRNA association with heavy polysomes, probably through the TCF7L2 5'-untranslated region (UTR), as determined by polysome fractionation and 5'UTR-reporter assays. Knockdown of TCF7L2 in MALAT1-overexpressing cells and HCC cell lines affected their metabolism and abolished their tumorigenic potential, suggesting that the effects of MALAT1 on glucose metabolism are essential for its oncogenic activity. Taken together, our findings suggest that MALAT1 contributes to HCC development and tumor progression by reprogramming tumor glucose metabolism. SIGNIFICANCE: These findings show that lncRNA MALAT1 contributes to HCC development by regulating cancer glucose metabolism, enhancing glycolysis, and inhibiting gluconeogenesis via elevated translation of the transcription factor TCF7L2.

SUN-311 Pervasive Hypoglycemia in the Unconventional Face of Ovarian Cancer

Background:Hypoglycemia can quickly become a medical emergency. Causes of hypoglycemic episodes are most commonly iatrogenic specifically in diabetic patients but can also be accredited to endogenous causes relating to neoplastic growth; this includes tumor induced secretions and/or increased tumor glucose metabolism(1). Tumor-related hypoglycemia is classically thought to present as islet cell tumors of neuroendocrine origin known as insulinomas which result in excessive insulin secretion. Rarely, hypoglycemia can be in the setting of hypoinsulinemia and high IGF2/IGF1 suggesting non-islet cell tumors specifically of mesenchymal or epithelial origin with paraneoplastic secretion of IGF2(2). Case:A 74 year old female with history of hypothyroidism and uterine cancer presents to the emergency department (ED) with episodic hypoglycemia with a BG of 23 in the setting of frequent bouts of palpitations and sweating for the last week. Prior to arrival in the ED she summoned EMS to her home for an episode of shaking and pale appearance at which time EMS evaluated her, administered D50 and her hypoglycemia resolved. She had a repeat episode which prompted her arrival to the ED later that day. She had no known history of diabetes and was admitted for further evaluation. On exam, abdomen a palpable solid suprapubic mass was felt just above the umbilical region. Subsequent CT revealed a 25 cm intra-abdominal predominantly cystic and solid mass extending above the level of the umbilicus. Labs revealed elevated CA-125:344.8, CEA:97.17, IGF2:217, IGF1:18 (IGF2/IGF1 = 12.06) which raised suspicion for ovarian cancer and Gynecology-Oncology ultimately performed bilateral salpingo-oophorectomy. Histology results postoperatively revealed high grade serous adenocarcinoma in the left adnexa. Paraneoplastic IGF2 elevation secondary to her tumor was the likely culprit of substantially increased IGF2:IGF1 ratio (>10x) as well as the likely cause of her refractory hypoglycemia. After complete resection of the tumor, the hypoglycemic state dissipated. Discussion: This case illustrates one of the more novel causes of hypoglycemia. It is customary to recognize hypoglycemia in the realm of diabetic treatment or islet-cell tumors, but unusual causes such as any non-islet cell tumors including serous adenocarcinomas should also be considered. Dutta et al. discusses 5 cases of non-islet cell tumor induced hypoglycemia with hypoglycemic symptoms leading to the diagnosis of the tumor in 3 of the 5 cases and striking IGF2/IGF1 found in each case(3). Furthermore, with accumulating literature beginning to show a causal relationship between IGF2 inducing non-islet cell tumors and hypoglycemia, this case supports the notion of routine IGF2/IGF1 laboratory evaluation in patients presenting with spontaneous hypoglycemia with no readily discernable cause(5).

Targeting LIN28B reprograms tumor glucose metabolism and acidic microenvironment to suppress cancer stemness and metastasis

The altered metabolism and acidic microenvironment plays an important role in promoting tumor malignant characteristics. A small population of cancer stem cells (CSCs) were considered as a therapy target to reserve tumor relapse, resistance, and metastasis. However, the molecular mechanism that regulates CSCs metabolism remains poorly understood. In this study, we demonstrate a fundamental role of stemness gene LIN28B in maintaining CSCs glycolysis metabolism. Using LIN28B-expressing cancer cell lines, we found that the rate of extracellular acidification, glucose uptake, and lactate secretion are all suppressed by LIN28B knockdown in vitro and in vivo. Importantly, metabolic analyses reveal that CSCs have enhanced aerobic glycolysis metabolic characteristics and the glycolytic product lactate further promotes cancer associated stemness properties. LIN28B silencing suppresses MYC expression that further increases miR-34a-5p level. Furthermore, the glycolysis metabolism of human breast cancer cell line MDA-MB-231 is suppressed by either MYC siRNA or miR-34a-5p mimic. Clinically, high MYC and low miR-34a-5p level are correlated with high LIN28B expression and poor prognosis in human breast cancer patients. Notably, blocking LIN28B/MYC/miR-34a-5p signaling pathway by LIN28B-specific inhibitor causes dramatic inhibition of tumor growth and metastasis in immunodeficient orthotopic mouse models of human breast cancer cell MDA-MB-231. Taken together, our findings offer a preclinical investigation of targeting LIN28B to suppress CSCs glycolysis metabolism and tumor progression that may improve the therapeutic benefit for cancer patients.

PIK3CA Mutational Status Is Associated with High Glycolytic Activity in ER+/HER2\u2212 Early Invasive Breast Cancer: a Molecular Imaging Study Using [18F]FDG PET/CT

PurposeIn PIK3CA mutant breast cancer, downstream hyperactivation of the PI3K/AKT/mTOR pathway may be associated with increased glycolysis of cancer cells. The purpose of this study was to investigate the functional association of PIK3CA mutational status and tumor glycolysis in invasive ER+/HER2− early breast cancer.ProceduresThis institutional review board-approved retrospective study included a dataset of 67 ER+/HER2− early breast cancer patients. All patients underwent 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/X-ray computed tomography ([18F]FDG PET/CT) and clinico-pathologic assessments as part of a prospective study. For this retrospective analysis, pyrosequencing was used to detect PIK3CA mutations of exons 4, 7, 9, and 20. Tumor glucose metabolism was assessed semi-quantitatively with [18F]FDG PET/CT using maximum standardized uptake values (SUVmax). SUVmax values were corrected for the partial volume effect, and metabolic tumor volume was calculated using the volume of interest automated lesion growing function 2D tumor size, i.e., maximum tumor diameter was assessed on concurrent pre-treatment contrast-enhanced magnetic resonance imaging.ResultsPIK3CA mutations were present in 45 % of all tumors. Mutations were associated with a small tumor diameter (p < 0.01) and with low nuclear grade (p = 0.04). Glycolytic activity was positively associated with nuclear grade (p = 0.01), proliferation (p = 0.002), regional lymph node metastasis (p = 0.015), and metabolic tumor volume (p = 0.001) but not with tumor size/T-stage. In invasive ductal carcinomas, median SUVmax was increased in PIK3CA-mutated compared to wild-type tumors; however, this increase did not reach statistical significance (p = 0.05). Multivariate analysis of invasive ductal carcinomas revealed [18F]FDG uptake to be independently associated with PIK3CA status (p = 0.002) and nuclear tumor grade (p = 0.046). Size, volume, and regional nodal status had no influence on glycolytic activity. PIK3CA mutational status did not influence glycolytic metabolism in lobular carcinomas. Glycolytic activity and PIK3CA mutational status had no significant influence on recurrence-free survival or disease-specific survival.ConclusionsIn ER+/HER2− invasive ductal carcinomas of the breast, glucose uptake is independently associated with PIK3CA mutations. Initial data suggest that [18F]FDG uptake reflects complex genomic alterations and may have the potential to be used as candidate biomarker for monitoring therapeutic response and resistance mechanisms in emerging therapies that target the PI3K/AKT/mTOR pathway.

Warburg and Krebs and related effects in cancer.

Warburg and coworkers' observation of altered glucose metabolism in tumours has been neglected for several decades, which, in part, was because of an initial misinterpretation of the basis of their finding. Following the realisation that genetic alterations are often linked to metabolism, and that the tumour micro-environment imposes different demands on cancer cells, has led to a reinvestigation of cancer metabolism in recent years. Increasing our understanding of the drivers and consequences of the Warburg effect in cancer and beyond will help to identify new therapeutic strategies as well as to identify new prognostic and therapeutic biomarkers. Here we discuss the initial findings of Warburg and coworkers regarding cancer cell glucose metabolism, how these studies came into focus again in recent years following the discovery of metabolic oncogenes, and the therapeutic potential that lies within targeting the altered metabolic phenotype in cancer. In addition, another essential nutrient in cancer metabolism, glutamine, will be discussed.

Correlation between tumor glucose metabolism and multiparametric functional MRI (IVIM and R2*) metrics in cervical carcinoma: Evidence from integrated 18 F-FDG PET/MR.

Multiparameter, multimodality 18 F-FDG PET/MRI holds great potential for the diagnosis of cervical cancer based on the correlation between tumor glucose metabolism and imaging parameters. To characterize the heterogeneity of tumor glucose metabolism by evaluating the correlation between 18 F-FDG uptake parameters and multiparametric functional MRI metrics in cervical carcinoma. Retrospective. Fifty-four patients with cervical carcinoma. Hybrid PET/MR (3T), multi-b DWI, and R2* mapping. The maximum and mean standardized uptake values (SUVmax and SUVmean , respectively) from PET and functional MRI metrics (D, D*, f, and R2*) were obtained. Cervical carcinoma tissues also underwent HIF-1α, VEGF, and GLUT-1 immunohistochemical staining. Single-factor Spearman rank and Pearson correlation analysis and multiple linear regression (MLR) analysis were applied. R2*, D, and f have different degrees of correlation (moderate, weak, moderately strong correlation, respectively) with SUVmax and SUVmean (r = 0.530 and 0.527, and P < 0.001 for R2*; r = -0.292 and -0.291, and P < 0.05 for D; r = 0.539 and 0.520, and P < 0.001 for f, respectively). Immunohistochemical staining showed that HIF-1α expression has a moderate degree of correlation with R2* (r = 0.491; P < 0.001); GLUT-1 expression was significantly correlated with SUVmax and SUVmean (r = 0.633 and 0.622; P < 0.001), and VEGF expression had a moderately strong correlation with f (r = 0.457; P = 0.001). If SUVmax is the dependent variable, MLR yields an R-squared value after adjustment (adjusted R-squared) = 0.358, and F = 10.833 (P < 0.001), and the fitting linear equation is Y (SUVmax ) = 9.184 + 0.161X1 (R2*)+50.343X2 (f)-4.780 (D). Otherwise, MLR yields the adjusted R-squared = 0.342, and F = 10.187 (P < 0.001), and the linear regression equation is Y (SUVmean ) = 5.925 + 0.102X1 (R2*)+28.029X2 (f)-2.907X3 (D). The functional MRI sequence parameters R2*, f, and D can provide information on the hypoxic condition, blood perfusion, and molecular diffusion of the tumor. 18 F-FDG PET/MR multi-imaging technique can be adopted to evaluate the heterogeneity of glucose metabolism in cervical carcinoma. 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;49:1704-1712.

CD147-mediated glucose metabolic regulation contributes to the predictive role of 18 F-FDG PET/CT imaging for EGFR-TKI treatment sensitivity in NSCLC.

The aim of this study is to investigate the role of CD147 in glucose metabolic regulation and its association with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment sensitivity prediction using 18 F-fluorodeoxyglucose (18 F-FDG) PET/CT imaging in non-small cell lung cancer (NSCLC). In this study, four human NSCLC cell lines with different EGFR-TKI responses were used to detect p-EGFR/EGFR and CD147 expression via Western blotting and flow cytometric analyses. Radioactive uptake of 18 F-FDG by established stable NSCLC cell lines (HCC827, H1975) with different levels of CD147 expression and the corresponding xenografts was assessed through γ-radioimmunoassays in vitro and micro-PET/CT imaging in vivo to study the role of CD147 in glucose metabolic reprogramming. Correlation analyses were performed to investigate the association between CD147 expression and PD-L1 expression in stable NSCLC cell lines. Higher CD147 expression was found in EGFR-TKI-sensitive NSCLC cell lines than in relatively resistant NSCLC cell lines (HCC827>PC9>A549>H1975). CD147 could promote 18 F-FDG uptake by HCC827 and H1975 cells in vitro and in vivo through an EGFR-initiated Akt/mTOR-dependent signaling pathway. Programmed cell death-ligand 1 (PD-L1) expression was positively correlated with CD147 expression in human NSCLC cell lines. EGFR-TKI treatment sensitivity prediction in NSCLC using 18 F-FDG PET/CT imaging significantly correlated with CD147-mediated glucose metabolic regulation via the Akt/mTOR-dependent pathway. Moreover, PD-L1 expression in NSCLC cell lines could be regulated by CD147, suggesting a potential immunosuppression induced by the upregulation of tumor glucose metabolism.

Microenvironmental control of glucose metabolism in tumors by regulation of pyruvate dehydrogenase.

During malignant progression cancer cells undergo a series of changes, which promote their survival, invasiveness and metastatic process. One of them is a change in glucose metabolism. Unlike normal cells, which mostly rely on the tricarboxylic acid cycle (TCA), many cancer types rely on glycolysis. Pyruvate dehydrogenase complex (PDC) is the gatekeeper enzyme between these two pathways and is responsible for converting pyruvate to acetyl-CoA, which can then be processed further in the TCA cycle. Its activity is regulated by PDP (pyruvate dehydrogenase phosphatases) and PDHK (pyruvate dehydrogenase kinases). Pyruvate dehydrogenase kinase exists in 4 tissue specific isoforms (PDHK1-4), the activities of which are regulated by different factors, including hormones, hypoxia and nutrients. PDHK1 and PDHK3 are active in the hypoxic tumor microenvironment and inhibit PDC, resulting in a decrease of mitochondrial function and activation of the glycolytic pathway. High PDHK1/3 expression is associated with worse prognosis in patients, which makes them a promising target for cancer therapy. However, a better understanding of PDC's enzymatic regulation in vivo and of the mechanisms of PDHK-mediated malignant progression is necessary for the design of better PDHK inhibitors and the selection of patients most likely to benefit from such inhibitors.

Artificial nutrition in patients with cancer has no impact on tumour glucose metabolism: Results of the PETANC Study

Nutrition support is recommended in cachexic patients with cancer. However, there is no clear evidence about its impact on tumour growth. Glycolysis, which is usually higher in cancer than normal cells, can be monitored by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging that is widely used for cancer staging and therapy efficacy assessment. Here, we used 18F-FDG PET/CT imaging to investigate whether artificial nutrition has an impact on tumour glucose metabolism in patients with cancer and cachexia. This prospective study included ten patients with histologically proven head and neck or oesophageal cancer. All patients underwent 18F-FDG PET/CT imaging at baseline and after (parenteral and/or enteral) nutrition support on average for 7 days. Tumour glucose metabolism changes were evaluated using static (SUVmax, SUVmean and SULpeak) and dynamic (glucose metabolic rate and transport constant rates, k) parameters computed from the 18F-FDG PET/CT data. Artificial nutrition (median energy intake of 21.83kcal/kg/day [13.16-45.90], protein intake of 0.84g/kg/day [0.56-1.64]) was administered. Eight patients (80%) received enteral nutrition and two patients (20%) parenteral support. Comparison of 18F-FDG PET/CT parameters did not highlight any significant difference in tumour glucose metabolism before and after the period of nutrition support. In cachexic patients with head and neck or oesophageal cancer, nutrition support administered according to the current guidelines shows no impact on tumour glucose metabolism, assessed by 18F-FDG PET/CT.

The Relationship Between Tumor Glucose Metabolism and Host Systemic Inflammatory Responses in Patients with Cancer: A Systematic Review

One of the most important and long recognized characteristics of tumor cells is their dysregulated cellular energetics with anaerobic driven glucose uptake. In patients with cancer, the prognostic value of the systemic inflammatory response has been well established, and the recent combination of PET and CT scanning combines the assessment of tumor physiologic activity with detailed anatomic localization. The aim of this study was to perform a systematic review of the assessment of the relationship between both the tumor and the host inflammatory responses using PET/CT. Methods: An extensive literature review using targeted subject headings was performed in the U.S. National Library of Medicine, the Excerpta Medica database, and the Cochrane Database of Systematic Reviews on March 31, 2018. On completion of the online search, the title and abstracts of each identified study were examined for relevance. Studies with duplicate datasets, not available in English, and that did not have full text availability were excluded. Full texts of relevant articles were obtained and were then examined to identify any further relevant articles. Results: Twelve studies containing 2,588 patients were included in the final analysis. All of the included studies used the 18F-FDG tracer in PET/CT imaging and had biochemical assessment of the systemic inflammatory response. Most studies showed a direct relationship between the tumor and bone marrow glucose uptake and host systemic inflammatory responses as measured by C-reactive protein (n = 2), albumin (n = 2), white cell count (n = 3), neutrophils (n = 2), and platelets (n = 2). Most of the studies (n = 8) also showed a direct relationship between tumor and bone marrow glucose uptake and poor outcomes. Conclusion: This review suggests a direct relationship between the tumor and bone marrow glucose uptake and host systemic inflammation. This may suggest new approaches for more optimal therapeutic targeting and monitoring strategies in patients with cancer.

2-Deoxy-2-[fluorine-18] fluoro-d-glucose uptake on positron emission tomography is associated with programmed death ligand-1 expression in patients with pulmonary adenocarcinoma

2-Deoxy-2-[fluorine-18] fluoro-d-glucose (18F-FDG) positron emission tomography (PET) is a useful modality for the assessment of tumour glucose metabolism by upregulation by hypoxia. Little is known whether the uptake of 18F-FDG within cancer cells is linked to the expression of programmed death ligand-1 (PD-L1), a predictor of anti–PD-1 antibody. We conducted a clinicopathological study to assess the expression of PD-L1 and tumour-infiltrating lymphocytes (TILs) in patients with surgically resected pulmonary adenocarcinoma (AC) who received preoperative 18F-FDG PET. A total of 315 patients with lung AC who received 18F-FDG PET were enrolled in the study. Tumour specimens were stained by immunohistochemistry for glucose transporter 1 (Glut1), hypoxia-inducible factor-1α (HIF-1α), PD-L1, CD4 and CD8. We assessed whether the uptake of 18F-FDG was correlated with clinicopathological variables. PD-L1 was highly expressed in 60% of all patients with AC, and the expression level was significantly correlated with 18F-FDG uptake, glucose metabolism and hypoxia. PD-L1 and the maximum standardised uptake value (SUVmax) were identified as independent prognostic predictors by multivariate analysis. In particular, PD-L1 could be a significant marker for predicting worse outcomes in AC patients with high 18F-FDG uptake but not in those with low 18F-FDG uptake. According to the epidermal growth factor receptor (EGFR) mutation status, the expression of PD-L1 was significantly correlated with SUVmax in patients with EGFR mutation, whereas, PD-L1 was a significant predictive negative factor in those with wild-type EGFR. 18F-FDG uptake was significantly correlated with PD-L1 expression, and the latter was closely linked to the presence of glucose metabolism and hypoxia in patients with pulmonary AC.

Clinical significance of SUVmax on preoperative 18F-fluorodeoxyglucose positron emission tomography in patients who underwent R0-esophagectomy for esophageal cancer.

ABSTRACTThe standardized uptake value (SUV) is a marker of tumor glucose metabolism, detected using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and may reflect tumor aggressiveness. The purpose of this study was to evaluate the clinical significance of maximum SUV (SUVmax) of primary esophageal cancer (EC) lesions. A total of 86 patients with EC who underwent pre-treatment FDG-PET and R0-resection were included in our study. The mean patient age was 65 years, and 87% were men. Histologically, cancers included squamous cell carcinomas, adenocarcinomas, and other tumors in 72, 3, and 11 patients, respectively. Preoperative chemotherapy with or without radiotherapy was performed in 4 and 37 patients, respectively. Measured patient outcomes included the correlation between the SUVmax of the primary EC lesion and clinicopathological factors in patients who did not undergo preoperative treatment (n = 45), and the investigation of relapse-free survival (RFS) according to SUVmax and the relationship between SUVmax and recurrence sites in all patients (n=86). The mean SUVmax was 8.9 ± 4.6, and SUVmax values significantly correlated with tumor invasion depth and stage. The 5-year RFS for the enrolled patients was 57%, and the RFS of patients with SUVmax < 7.0 was better than that of patients with SUVmax ≥ 7.0, with a marginal difference (p = 0.0892). Lymph node recurrences were significantly more common in patients with SUVmax ≥ 7.0, compared to patients with SUVmax < 7.0. Therefore, the SUVmax value of the primary EC lesion before preoperative treatment may be predictive of RFS and lymph node recurrence.

MiR‑199a‑3p/Sp1/LDHA axis controls aerobic glycolysis in testicular tumor cells.

Aerobic glycolysis is one of the characteristics of tumor metabolism and contributes to the development of tumors. Studies have identified that microRNA (miRNA/miR) serves an important role in glucose metabolism of tumors. miR‑199a‑3p is a member of the miR‑199a family that controls the outcomes of cell survival and death processes, and previous studies have indicated that the expression of miR‑199a‑3p is low and may be an inhibitor in several cancer types, including testicular tumors. The present study discussed the role and underlying mechanism of miR‑199a‑3p in aerobic glycolysis of Ntera‑2 cells and identified its downstream factors. Firstly, miR‑199a‑3p exhibited an inhibitory effect on lactic acid production, glucose intake, and reactive oxygen species (ROS) and adenosine 5'‑triphosphate (ATP) levels in Ntera‑2 cells. Then, using bioinformatics, recombinant construction and a dual luciferase reporter gene system, transcription factor Specificity protein 1 (Sp1) was determined as the direct target of miR‑199a‑3p. Also, downregulation of Sp1 by RNA interference decreased lactic acid production, glucose intake, and ROS and ATP levels in Ntera‑2 cells. Subsequently, through a functional rescue experiment, it was identified that the overexpression of Sp1 may abate the inhibition of miR‑199a‑3p on glucose metabolism, with the exception of ATP level, suggesting a reciprocal association between Sp1 and miR‑199a‑3p. Finally, it was determined that miR‑199a‑3p overexpression and Sp1 knockdown decreased lactate dehydrogenaseA (LDHA) protein expression, which indicated that LDHA is a downstream target of the miR‑199a‑3p/Sp1 signaling pathway. To additionally verify the regulation of LDHA expression by 199a‑3p/Sp1, a LDHA promoter reporter plasmid was generated and the high activity of the promoter, which contained 3 potential Sp1 binding elements, was confirmed. In addition, the overexpression of Sp1 led to the increased activity of the LDHA promoter, whereas knockdown of Sp1 exhibited the opposite effect. Therefore, the results of the present study demonstrated that miR‑199a‑3p can inhibit LDHA expression by downregulating Sp1, and provided mechanistic evidence supporting the existence of a novel miR‑199a‑3p/Sp1/LDHA axis and its critical contribution to aerobic glycolysis in testicular cancer cells.

Effects of a Ketogenic Diet on [18F]FDG-PET Imaging in a Mouse Model of Lung Cancer.

Myocardial uptake can hamper visualization of lung tumors, atherosclerotic plaques, and inflammatory diseases in 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) studies because it leads to spillover in adjacent structures. Several preparatory pre-imaging protocols (including dietary restrictions and drugs) have been proposed to decrease physiological [18F]FDG uptake by the heart, although their effect on tumor glucose metabolism remains largely unknown. The objective of this study was to assess the effects of a ketogenic diet (as an alternative protocol to fasting) on tumor glucose metabolism assessed by [18F]FDG positron emission tomography (PET) in a mouse model of lung cancer. PET scans were performed 60min after injection of 18.5MBq of [18F]FDG. PET data were collected for 45min, and an x-ray computed tomograph (CT) image was acquired after the PET scan. A PET/CT study was obtained for each mouse after fasting and after the ketogenic diet. Quantitative data were obtained from regions of interest in the left ventricular myocardium and lung tumor. Three days on a ketogenic diet decreased mean standard uptake value (SUVmean) in the myocardium (SUVmean 0.95 ± 0.36) more than one night of fasting (SUVmean 1.64 ± 0.93). Tumor uptake did not change under either dietary condition. These results show that 3days on high-fat diets prior to [18F]FDG-PET imaging does not change tumor glucose metabolism compared with one night of fasting, although high-fat diets suppress myocardial [18F]FDG uptake better than fasting.

CT quantitative analysis study for angiogenesis, and degree of ischemic necrosis and glucose metabolite in non-small cell lung cancer.

We aimed at exploring the feasibility of noninvasive late arterial phase enhanced CT imaging in evaluating tumor angiogenesis, ischemic necrosis, and glucose metabolism, thereby providing pathological information for the comprehensive treatment plan in non-small cell lung cancer (NSCLC). 52 cases of NSCLC were enrolled in this study. The mean ischemia necrosis CT quantitative value (INCTQ) and CT enhanced value (CTe) of the tumor were determined, and the immunohistochemical staining of factors relating to tumor angiogenesis, ischemic necrosis and glucose metabolism, including VEGF, VEGFR-2, HIF-1α, CAIX, GLUT1, and GLUT3, were conducted. The mean INCTQ values of different expression grades of VEGF, VEGFR-2, HIF-1α, and CAIX have no significant difference, but the mean INCTQ values of different expression grades of GLUT1 or GLUT3 have significant differences (p < 0.001), respectively. However, INCTQ value has a positive correlation with CAIX expression. In addition, CTe value was positively correlated with VEGF. To sum up, late arterial phase CT enhanced images of NSCLC not only can assess the tumor angiogenesis, but also can reflect the degree of ischemic necrosis, effectively reflecting the level of glucose metabolism in tumor and tumor angiogenesis, for the comprehensive treatment program.

Abstract 5487: Targeting glycolysis for the treatment of cancer

Abstract Tumors exhibit markedly increased glucose uptake and glycolysis and this metabolic phenotype serves to satisfy their increased requirement for energy and biosynthetic intermediates. Tumor glucose metabolism is stimulated in part by fructose-2,6-bisphosphate (F26BP), which is the product of a family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) and allosterically activates a key glycolytic enzyme, 6-phosphofructo-1-kinase (PFK-1). Previous studies have found the PFKFB3 family member to be a dominant source of F26BP in cancer cells due to a high kinase activity, expression in multiple tumor types and the inhibition of tumor growth by specific PFKFB3 inhibitors including a compound, PFK158, that is currently under evaluation in a phase I trial. Recent data, however, indicate that the PFKFB4 enzyme plays a significant role in regulating glucose metabolism in neoplastic cells. We have found that PFKFB4 is highly expressed in multiple cancers, strongly induced by HIF-1α, and that its suppression markedly reduced F26BP and glycolytic flux, increased apoptosis and inhibited growth of xenograft tumors in vivo, thus providing strong rationale for the development of antineoplastic agents selectively targeting PFKFB4. Using virtual screening, we have discovered a first-in-class small molecule inhibitor of PFKFB4, termed 5MPN, that selectively inhibits recombinant PFKFB4 activity with a resultant decrease in F26BP, glycolytic flux and cancer cell growth in vitro and markedly reduces the growth of established tumors without systemic toxicity. During our studies, we unexpectedly observed that PFKFB4 expression is increased by PFKFB3 inhibition, suggesting that PFKFB4 may compensate for decreased PFKFB3 expression and activity. We examined the effects of simultaneous silencing of PFKFB4 and PFKFB3 on cancer cell lines and found that co-knockdown led to a significant decrease in cell viability and glycolysis and to a near-complete abrogation of anchorage-independent growth in vitro. We additionally examined the effect of simultaneous inhibition of PFKFB4 and PFKFB3 using 5MPN and several PFKFB3 inhibitors in vitro and found a synergistic increase in cell death. Taken together, our data indicate that targeting PFKFB4 may be a viable therapeutic option against cancer and strongly support the further development of PFKFB4 small-molecule inhibitors as well as the co-targeting of PFKFB4 and PFKFB3 as potential strategies for the treatment of cancer. Citation Format: Jason Chesney, Aubrey Mojesky, Yoannis Imbert-Fernandez, John Trent, Sucheta Telang. Targeting glycolysis for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5487.

Inhibition of Pyruvate Dehydrogenase Kinase as a Therapeutic Strategy against Cancer.

Cancer cells alter their metabolism to support the uninterrupted supply of biosynthetic molecules required for continuous proliferation. Glucose metabolism is frequently reprogrammed in several tumors in addition to fatty acid, amino acid and glutamine metabolism. Pyruvate Dehydrogenase Kinase (PDK) is a gatekeeper enzyme involved in altered glucose metabolism in tumors. There are four isoforms of PDK (1 to 4) in humans. PDK phosphorylates E1α subunit of pyruvate dehydrogenase complex (PDC) and inactivates it. PDC decarboxylates pyruvate to acetyl CoA, which is further metabolized in mitochondria. Overexpression of PDK was observed in several tumors and is frequently associated with chemotherapy related drug resistance, invasion and metastasis. Elevated expression of PDK leads to a shift in glucose metabolism towards glycolysis instead of oxidative phosphorylation. This review summarizes recent literature related to the role of PDKs in cancer and their inhibition as a strategy. In particular, we discuss the role of PDK in tumor progression, metabolic reprogramming in stem cells, and their regulation by miRNAs and lncRNAs, oncogenes and tumor suppressors. Further, we review strategies aimed at targeting PDK to halt tumor growth and progression.

Association of 18F-FDG uptake on PET with PD-L1 expression in patients with non-small cell lung cancer.

e24138Background: 2-Deoxy-2-[fluorine-18] fluoro-D-glucose (18F-FDG) positron emission tomography (PET) is a useful modality for the assessment of tumor glucose metabolism by up-regulation by hypox...