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https://www.readbyqxmd.com/read/28875379/tumor-vessel-disintegration-by-maximum-tolerable-pfkfb3-blockade
#1
Lena-Christin Conradi, Aleksandra Brajic, Anna Rita Cantelmo, Ann Bouché, Joanna Kalucka, Andreas Pircher, Ulrike Brüning, Laure-Anne Teuwen, Stefan Vinckier, Bart Ghesquière, Mieke Dewerchin, Peter Carmeliet
Blockade of the glycolytic activator PFKFB3 in cancer cells (using a maximum tolerable dose of 70 mg/kg of the PFKFB3 blocker 3PO) inhibits tumor growth in preclinical models and is currently being tested as a novel anticancer treatment in phase I clinical trials. However, a detailed preclinical analysis of the effects of such maximum tolerable dose of a PFKFB3 blocker on the tumor vasculature is lacking, even though tumor endothelial cells are hyper-glycolytic. We report here that a high dose of 3PO (70 mg/kg), which inhibits cancer cell proliferation and reduces primary tumor growth, causes tumor vessel disintegration, suppresses endothelial cell growth for protracted periods, (model-dependently) aggravates tumor hypoxia, and compromises vascular barrier integrity, thereby rendering tumor vessels more leaky and facilitating cancer cell intravasation and dissemination...
September 5, 2017: Angiogenesis
https://www.readbyqxmd.com/read/28875330/liposomes-co-loaded-with-6-phosphofructo-2-kinase-fructose-2-6-biphosphatase-3-pfkfb3-shrna-plasmid-and-docetaxel-for-the-treatment-of-non-small-cell-lung-cancer
#2
Nusrat Chowdhury, Imran Vhora, Ketan Patel, Ravi Doddapaneni, Arindam Mondal, Mandip Singh
PURPOSE: Non-small cell lung cancer is the leading cause of cancer related deaths globally. Considering the side effects and diminishing chemosensitivity to chemotherapy, novel treatment approaches are sought. Hence, we aim to develop a liposomal co-delivery system of pDNA expressing shRNA against PFKFB3 (pshPFKFB3) and docetaxel (DTX). METHODS: Cationic DTX liposomes complexed with pshPFKFB3 (PSH-DL) were developed. In vitro cell line studies were performed to evaluate transfection, PFKFB3 mRNA silencing, cytotoxicity, pGP inhibition, and protein markers expression...
September 5, 2017: Pharmaceutical Research
https://www.readbyqxmd.com/read/28857200/by-inhibiting-pfkfb3-aspirin-overcomes-sorafenib-resistance-in-hepatocellular-carcinoma
#3
Sainan Li, Weiqi Dai, Wenhui Mo, Jingjing Li, Jiao Feng, Liwei Wu, Tong Liu, Qiang Yu, Shizan Xu, Wenwen Wang, Xiya Lu, Qinghui Zhang, Kan Chen, Yujing Xia, Jie Lu, Yingqun Zhou, Xiaoming Fan, Ling Xu, Chuanyong Guo
Hepatocellular carcinoma (HCC) is one of the few cancers with a continuous increase in incidence and mortality. Drug resistance is a major problem in the treatment of HCC. In the present study, two sorafenib-resistant HCC cell lines and a nude mouse subcutaneously tumor model were used to explore the possible mechanisms leading to sorafenib resistance, and to investigate whether aspirin could increase the sensitivity of hepatoma cells to sorafenib. The combination of aspirin and sorafenib resulted in a synergistic antitumor effect against liver tumors both in vitro and in vivo...
August 31, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28834297/tgf-%C3%AE-1-targets-smad-p38-mapk-and-pi3k-akt-signaling-pathways-to-induce-pfkfb3-gene-expression-and-glycolysis-in-glioblastoma-cells
#4
Ana Rodríguez-García, Paula Samsó, Pere Fontova, Helga Simon-Molas, Anna Manzano, Esther Castaño, Jose Luis Rosa, Ubaldo Martinez-Outshoorn, Francesc Ventura, Àurea Navarro-Sabaté, Ramon Bartrons
In human cancers, TGF-β1 plays a dual role by acting as both a tumor suppressor and a promoter of tumor metastasis. Although TGF-β1 contributes to the metabolic reprogramming of cancer cells and tumor-associated stromal cells, little is known of the molecular mechanisms connecting this cytokine with enhanced glycolysis. PFKFB3 is a homodymeric bifunctional enzyme, belonging to the family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases, that controls the conversion of fructose-6-phosphate to fructose-2,6-bisphosphate...
August 20, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28765514/the-molecular-basis-of-targeting-pfkfb3-as-a-therapeutic-strategy-against-cancer
#5
REVIEW
Luo Lu, Yaoyu Chen, Yu Zhu
6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatases (PFKFBs) are bifunctional enzymes which regulate the transformation between fructose-2, 6-bisphosphate (F2, 6BP) and fructose-6-phosphate (F6P) in the process of glucose metabolism. Among the four isozymes (PFKFB1-4), PFKFB3 has stronger kinase activity than phosphatase activity, resulting in the synthesis of F2, 6BP and the promotion of glycolysis. Additionally, PFKFB3 plays a key role in cell cycle regulation. It has been confirmed that PFKFB3 is upregulated in a variety of tumor cells, and inhibition of it results in suppression of the growth of tumor cells by downregulating the glycolytic flux...
July 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28762754/flow-responsive-vegfr-pkc%C3%A9-signaling-mediates-glycolytic-metabolites-for-vascular-repair
#6
Kyung In Baek, Rongsong Li, Nelson Jen, Howard Choi, Amir Kaboodrangi, Peipei Ping, David Liem, Tyler Beebe, Tzung K Hsiai
Aims - Hemodynamic shear stress participates in maintaining vascular redox status. Elucidating flow-mediated endothelial metabolites enables us to discover metabolic biomarkers and therapeutic targets. We posited that flow-responsive VEGF receptor-PKCɛ-PFKFB3 signaling modulates glycolytic metabolites for vascular repair. Results - Bidirectional oscillatory flow (OSS: 0.1 ± 3 dyne·cm<sup>-2</sup> at 1 Hz) up-regulated VEGFR-dependent PKCɛ expression to a greater degree than did unidirectional pulsatile flow (PSS: 23 ± 8 dyne·cm<sup>-2</sup> at 1 Hz) in human aortic endothelial cells (HAEC) (<i>p < 0...
August 1, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28644415/genome-wide-association-study-of-dietary-pattern-scores
#7
Frédéric Guénard, Annie Bouchard-Mercier, Iwona Rudkowska, Simone Lemieux, Patrick Couture, Marie-Claude Vohl
Dietary patterns, representing global food supplies rather than specific nutrients or food intakes, have been associated with cardiovascular disease (CVD) incidence and mortality. The contribution of genetic factors in the determination of food intakes, preferences and dietary patterns has been previously established. The current study aimed to identify novel genetic factors associated with reported dietary pattern scores. Reported dietary patterns scores were derived from reported dietary intakes for the preceding month and were obtained through a food frequency questionnaire and genome-wide association study (GWAS) conducted in a study sample of 141 individuals...
June 23, 2017: Nutrients
https://www.readbyqxmd.com/read/28576491/blockage-of-glycolysis-by-targeting-pfkfb3-alleviates-sepsis-related-acute-lung-injury-via-suppressing-inflammation-and-apoptosis-of-alveolar-epithelial-cells
#8
Yuanqi Gong, Haibing Lan, Zhihong Yu, Meng Wang, Shu Wang, Yu Chen, Haiwei Rao, Jingying Li, Zhiyong Sheng, Jianghua Shao
Sepsis-related acute lung injury (ALI) is characterized by excessive lung inflammation and apoptosis of alveolar epithelial cells resulting in acute hypoxemic respiratory failure. Recent studies indicated that anaerobic glycolysis play an important role in sepsis. However, whether inhibition of aerobic glycolysis exhibits beneficial effect on sepsis-induced ALI is not known. In vivo, a cecal ligation and puncture (CLP)-induced ALI mouse model was set up and mice treated with glycolytic inhibitor 3PO after CLP...
September 16, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28571757/hmgb1-promotes-hlf-1-proliferation-and-ecm-production-through-activating-hif1-%C3%AE-regulated-aerobic-glycolysis
#9
JianNing Xu, JingYing Li, ZhiHong Yu, HaiWei Rao, Shu Wang, HaiBing Lan
Aerobic glycolysis is a crucial event in fibroblast differentiation, and extracellular matrix (ECM) production in the progression of pulmonary fibrosis (PF). Abnormal high mobility group protein B1 (HMGB1) activation is involved in the pathogenesis of PF. However, whether aerobic glycolysis contributes to HMGB1-induced fibroblast proliferation and ECM production in PF has not yet been determined. In this study, we investigated the effects of HMGB1 on human embryonic lung fibroblast (HLF-1) proliferation, ECM production, and aerobic glycolysis...
August 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28559290/a-role-for-pfkfb3-ipfk2-in-metformin-suppression-of-adipocyte-inflammatory-responses
#10
Ting Qi, Yanming Chen, Honggui Li, Ya Pei, Shih-Lung Woo, Xin Guo, Jiajia Zhao, Xiaoxian Qian, Joseph Awika, Yuqing Huo, Chaodong Wu
Metformin improves obesity-associated metabolic dysregulation, but has controversial effects on adipose tissue inflammation. The objective of the study is to examine the direct effect of metformin on adipocyte inflammatory responses and elucidate the underlying mechanisms. Adipocytes were differentiated from 3T3-L1 cells and treated with metformin at various doses and for different time periods. The treated cells were examined for the proinflammatory responses, as well as the phosphorylation states of AMPK and the expression of PFKFB3/iPFK2...
July 2017: Journal of Molecular Endocrinology
https://www.readbyqxmd.com/read/28395898/p63-adjusts-sugar-taste-of-epidermal%C3%A2-layers
#11
REVIEW
Ivano Amelio, Gerry Melino, Eleonora Candi
p63 is a master regulator of epidermal biology, sustaining stemness and renewal capacity of the proliferating keratinocyte compartment. Hamanaka and Mutlu propose that p63 regulates the keratinocyte proliferation/differentiation switch by affecting the cellular glycolic rate through a direct transcriptional regulation of the metabolic enzyme PFKFB3. This finding sheds light on mechanisms underlining p63 function in the skin and suggests a role for energetic metabolism in epidermal biology.
June 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28348059/the-glycolytic-enzyme-pfkfb3-is-involved-in-estrogen-mediated-angiogenesis-via-gper1
#12
Annalisa Trenti, Serena Tedesco, Carlotta Boscaro, Nicola Ferri, Andrea Cignarella, Lucia Trevisi, Chiara Bolego
The endogenous estrogen 17β-estradiol (E2) is a key factor in promoting endothelial healing and angiogenesis. Recently, proangiogenic signals including vascular endothelial growth factor and others have been shown to converge in endothelial cell metabolism. Because inhibition of the glycolytic enzyme activator phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3) reduces pathologic angiogenesis and estrogen receptor (ER) signaling stimulates glucose uptake and glycolysis by inducing PFKFB3 in breast cancer, we hypothesized that E2 triggers angiogenesis in endothelial cells via rapid ER signaling that requires PFKFB3 as a downstream effector...
June 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28316886/identification-of-dysregulated-genes-in-rheumatoid-arthritis-based-on-bioinformatics-analysis
#13
Ruihu Hao, Haiwei Du, Lin Guo, Fengde Tian, Ning An, Tiejun Yang, Changcheng Wang, Bo Wang, Zihao Zhou
BACKGROUND: Rheumatoid arthritis (RA) is a chronic auto-inflammatory disorder of joints. The present study aimed to identify the key genes in RA for better understanding the underlying mechanisms of RA. METHODS: The integrated analysis of expression profiling was conducted to identify differentially expressed genes (DEGs) in RA. Moreover, functional annotation, protein-protein interaction (PPI) network and transcription factor (TF) regulatory network construction were applied for exploring the potential biological roles of DEGs in RA...
2017: PeerJ
https://www.readbyqxmd.com/read/28239846/inhibition-of-6-phosphofructo-2-kinase-suppresses-fibroblast-like-synoviocytes-mediated-synovial-inflammation-and-joint-destruction-in-rheumatoid-arthritis
#14
Yaoyao Zou, Shan Zeng, Mingcheng Huang, Qian Qiu, Youjun Xiao, Maohua Shi, Zhongping Zhan, Liuqin Liang, Xiuyan Yang, Hanshi Xu
BACKGROUND AND PURPOSE: Abnormal glycolytic metabolism contributes to joint inflammation in rheumatoid arthritis (RA). The aims of this study were to investigate the role of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a bifunctional enzyme that controls the glycolytic rate, in regulating fibroblast-like synoviocyte (FLS)-mediated synovial inflammation and invasiveness in RA. EXPERIMENTAL APPROACH: A specific inhibitor of PFKFB3, PFK15, and siRNA were used to evaluate the role of PFKFB3...
May 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28235572/role-of-akt-pkb-and-pfkfb-isoenzymes-in-the-control-of-glycolysis-cell-proliferation-and-protein-synthesis-in-mitogen-stimulated-thymocytes
#15
Amina Houddane, Laurent Bultot, Laura Novellasdemunt, Manuel Johanns, Marie-Agnès Gueuning, Didier Vertommen, Pierre G Coulie, Ramon Bartrons, Louis Hue, Mark H Rider
Proliferating cells depend on glycolysis mainly to supply precursors for macromolecular synthesis. Fructose 2,6-bisphosphate (Fru-2,6-P2) is the most potent positive allosteric effector of 6-phosphofructo-1-kinase (PFK-1), and hence of glycolysis. Mitogen stimulation of rat thymocytes with concanavalin A (ConA) led to time-dependent increases in lactate accumulation (6-fold), Fru-2,6-P2 content (4-fold), 6-phosphofructo-2-kinase (PFK-2)/fructose-2,6-bisphosphatase isoenzyme 3 and 4 (PFKFB3 and PFKFB4) protein levels (~2-fold and ~15-fold, respectively) and rates of cell proliferation (~40-fold) and protein synthesis (10-fold) after 68h of incubation compared with resting cells...
June 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28212191/endothelial-cell-metabolism-an-update-anno-2017
#16
Laure-Anne Teuwen, Nihed Draoui, Charlotte Dubois, Peter Carmeliet
PURPOSE OF REVIEW: Endothelial cell metabolism has recently emerged as an important coregulator of angiogenesis and is therefore a promising new target in various angiogenesis-associated illnesses, like cancer. In this review, we discuss recent insights in endothelial cell metabolism in both physiological and pathological conditions and discuss possible translational implications. RECENT FINDINGS: Two metabolic pathways that determine the performance of endothelial cells are glycolysis and fatty acid oxidation (FAO)...
May 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28173976/targeting-pfkfb3-in-the-endothelium-for-cancer-therapy
#17
Qi Yang, Peng Hou
In a recent article published in Cancer Cell, Cantelmo et al. showed that inhibition of endothelium glycolysis by targeting 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) significantly impaired tumor metastasis by normalizing tumor vessels. In addition, as a promising therapeutic strategy, tumor vessel normalization by PFKFB3 blockade also improved the delivery and efficacy of chemotherapy.
March 2017: Trends in Molecular Medicine
https://www.readbyqxmd.com/read/28161638/6-phosphofructo-2-kinase-fructose-2-6-bisphosphatase-3-is-required-for-transforming-growth-factor-%C3%AE-1-enhanced-invasion-of-panc1-cells-in%C3%A2-vitro
#18
Abdullah Yalcin, Tugba H Solakoglu, Selahattin C Ozcan, Saime Guzel, Sabire Peker, Serap Celikler, Basak D Balaban, Elif Sevinc, Yunus Gurpinar, Jason A Chesney
Transforming growth factor β1 (TGFβ1) is a well-established inducer of the epithelial-mesenchymal transition (EMT) that is essential for the acquisition of malignant properties, such as invasion, in tumor cells. Although recent studies suggest that the EMT in tumor cells is associated with reprogramming of energy metabolism and TGFβ1 has been shown to stimulate glycolysis in multiple primary cell lines, little is known about TGFβ1's effect on glycolysis and glycolytic regulators in transformed cells. Given the known regulatory role of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase-3 (PFKFB3) in glycolysis and association of glycolytic activity with malignant features such as invasion, we sought to investigate whether TGFβ1 regulates PFKFB3 expression and if PFKFB3 is involved in the TGFβ1-mediated increase in the invasive ability of the Panc1 cell cline-a well-established model of TGFβ1-initiated EMT...
March 11, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28152500/loss-of-pfkfb4-induces-cell-death-in-mitotically-arrested-ovarian-cancer-cells
#19
Charlotte Taylor, David Mannion, Fabrizio Miranda, Mohammad Karaminejadranjbar, Sandra Herrero-Gonzalez, Karin Hellner, Yiyan Zheng, Geoffrey Bartholomeusz, Robert C Bast, Ahmed Ashour Ahmed
Taxanes represent some of the most commonly used chemotherapeutic agents for ovarian cancer treatment. However, they are only effective in approximately 40% of patients. Novel therapeutic strategies are required to potentiate their effect and improve patient outcome. A hallmark of many cancers is the constitutive activation of the PI3K/AKT pathway, which drives cell survival and metabolism. We discovered a striking decrease in AKT activity coupled with a significant reduction in glucose 6-phosphate and ATP levels during mitotic arrest in the majority of ovarian cancer cell lines tested, indicating a potential metabolic vulnerability...
March 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28108301/pfkfb3-a-direct-target-of-p63-is-required-for-proliferation-and-inhibits-differentiation-in-epidermal-keratinocytes
#20
Robert B Hamanaka, Gökhan M Mutlu
p63 is a transcription factor essential for epidermal development and homeostasis. p63 is a member of the p53 family of transcription factors, which are increasingly understood to be regulators of cellular metabolism. How p63 regulates metabolism in epidermal keratinocytes is incompletely understood, and it is unknown whether glycolytic regulation is essential to maintain the balance between proliferation and differentiation within the epidermis. We found that p63 promotes glycolytic metabolism in epidermal keratinocytes...
June 2017: Journal of Investigative Dermatology
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