scholarly journals Hyaluronic acid fuels pancreatic cancer cell growth

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Peter K Kim ◽  
Christopher J Halbrook ◽  
Samuel A Kerk ◽  
Megan Radyk ◽  
Stephanie Wisner ◽  
...  
Keyword(s):  
Hyaluronic Acid ◽  
Biosynthetic Pathway ◽  
Human Tumor ◽  
Pancreatic Tumors ◽  
Cancer Cell Growth ◽  
Hexosamine Biosynthetic Pathway ◽  
Carbohydrate Polymer ◽  
Rate Limiting ◽  
Proliferation In Vitro

Rewired metabolism is a hallmark of pancreatic ductal adenocarcinomas (PDA). Previously, we demonstrated that PDA cells enhance glycosylation precursor biogenesis through the hexosamine biosynthetic pathway (HBP) via activation of the rate limiting enzyme, glutamine-fructose 6-phosphate amidotransferase 1 (GFAT1). Here, we genetically ablated GFAT1 in human PDA cell lines, which completely blocked proliferation in vitro and led to cell death. In contrast, GFAT1 knockout did not preclude the growth of human tumor xenografts in mice, suggesting that cancer cells can maintain fidelity of glycosylation precursor pools by scavenging nutrients from the tumor microenvironment. We found that hyaluronic acid (HA), an abundant carbohydrate polymer in pancreatic tumors composed of repeating N-acetyl-glucosamine (GlcNAc) and glucuronic acid sugars, can bypass GFAT1 to refuel the HBP via the GlcNAc salvage pathway. Together, these data show HA can serve as a nutrient fueling PDA metabolism beyond its previously appreciated structural and signaling roles.

scholarly journals Hyaluronic Acid Fuels Pancreatic Cancer Growth

2020 ◽  
Author(s):  
Peter K. Kim ◽  
Christopher J. Halbrook ◽  
Samuel A. Kerk ◽  
Stephanie Wisner ◽  
Daniel M. Kremer ◽  
...  
Keyword(s):  
Hyaluronic Acid ◽  
Biosynthetic Pathway ◽  
Pancreatic Tumors ◽  
Wild Type ◽  
Salvage Pathway ◽  
Hexosamine Biosynthetic Pathway ◽  
Carbohydrate Polymer ◽  
Rate Limiting ◽  
Proliferation In Vitro

AbstractRewired metabolism is a hallmark of pancreatic ductal adenocarcinomas (PDA). Previously, we demonstrated that PDA cells enhance glycosylation precursor biogenesis through the hexosamine biosynthetic pathway (HBP) via activation of the rate limiting enzyme, glutamine-fructose 6-phosphate amidotransferase 1 (GFAT1). Here, we genetically ablated GFAT1 in PDA cell lines, which completely blocked proliferation in vitro and led to cell death. In contrast, GFAT1 knockout did not impair tumor growth, suggesting that cancer cells can maintain fidelity of glycosylation precursor pools by scavenging nutrients from the tumor microenvironment. Here, we show that hyaluronic acid (HA), an abundant carbohydrate polymer in pancreatic tumors composed of repeating N-acetyl-glucosamine (GlcNAc) and glucuronic acid sugars, can bypass GFAT1 to refuel the HBP via the GlcNAc salvage pathway. Furthermore, HA facilitates proliferation in nutrient-starved wild-type PDA. Together, these data show HA can serve as a nutrient fueling PDA metabolism beyond its previously appreciated structural and signaling roles.

scholarly journals Antileishmanial Effect of 3-Aminooxy-1-Aminopropane Is Due to Polyamine Depletion

2006 ◽  
Vol 51 (2) ◽  
pp. 528-534 ◽  
Author(s):  
Sushma Singh ◽  
Angana Mukherjee ◽  
Alex R. Khomutov ◽  
Lo Persson ◽  
Olle Heby ◽  
...  
Keyword(s):  
Biosynthetic Pathway ◽  
Leishmania Donovani ◽  
Clinical Isolates ◽  
Growth And Survival ◽  
Antiproliferative Effects ◽  
Cell Growth And Differentiation ◽  
First Time ◽  
Rate Limiting ◽  
Sodium Antimony Gluconate

ABSTRACT The polyamines putrescine, spermidine, and spermine are organic cations that are required for cell growth and differentiation. Ornithine decarboxylase (ODC), the first and rate-limiting enzyme in the polyamine biosynthetic pathway, catalyzes the conversion of ornithine to putrescine. As the polyamine biosynthetic pathway is essential for the growth and survival of Leishmania donovani, the causative agent of visceral leishmaniasis, inhibition of the pathway is an important leishmaniacidal strategy. In the present study, we examined for the first time the effects of 3-aminooxy-1-aminopropane (APA), an ODC inhibitor, on the growth of L. donovani. APA inhibited the growth of both promastigotes in vitro and amastigotes in the macrophage model, with the 50% inhibitory concentrations being 42 and 5 μM, respectively. However, concentrations of APA up to 200 μM did not affect the viability of macrophages. The effects of APA were completely abolished by the addition of putrescine or spermidine. APA induced a significant decrease in ODC activity and putrescine, spermidine, and trypanothione levels in L. donovani promastigotes. Parasites were transfected with an episomal ODC construct, and these ODC overexpressers exhibited significant resistance to APA and were concomitantly resistant to sodium antimony gluconate (Pentostam), indicating a role for ODC overexpression in antimonial drug resistance. Clinical isolates with sodium antimony gluconate resistance were also found to overexpress ODC and to have significant increases in putrescine and spermidine levels. However, no increase in trypanothione levels was observed. The ODC overexpression in these clinical isolates alleviated the antiproliferative effects of APA. Collectively, our results demonstrate that APA is a potent inhibitor of L. donovani growth and that its leishmaniacidal effect is due to inhibition of ODC.

scholarly journals The Deubiquitinase USP39 Promotes ESCC Tumorigenesis Through Pre-mRNA Splicing of the mTORC2 Component Rictor

2021 ◽  
Vol 11 ◽  
Author(s):  
Yuan Zhao ◽  
Huiwu Geng ◽  
Gang Liu ◽  
Qiang Ji ◽  
Xiaomin Cheng ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Human Tumor ◽  
Molecular Complexes ◽  
Clinicopathological Characteristics ◽  
Mrna Splicing ◽  
Cancer Cell Growth ◽  
Tumorigenesis And Progression ◽  
Differentiation Status ◽  
Biochemical Analyses

Spliceosomes are large RNA-protein molecular complexes which mediate splicing of pre-mRNA in eukaryotic cells. Their function is frequently altered in cancer, providing opportunities for novel therapeutic approaches. The ubiquitin specific protease 39 (USP39) is a highly conserved deubiquitylation family member that plays an essential role in pre-mRNA splicing where it serves to assemble the mature spliceosome complex. Previous studies have reported that USP39 acts in an oncogenic manner where it contributes to cancer progression and predicts poor prognosis in various human tumor types. Here we report that USP39 is differentially upregulated in human esophageal squamous cell carcinoma (ESCC) and its expression is significantly associated with clinicopathological characteristics including differentiation status and TNM stage. We found the USP39 upregulation was maintained in ESCC cell lines where it functioned to promote cancer cell growth in vitro and in xenografts. RNA-seq analyses identified that mTOR pathway activation was affected by shRNA-mediated silencing of USP39. Subsequent biochemical analyses demonstrated that USP39 regulates the activity of mTORC2 by selectively enhancing the splicing and maturation of Rictor mRNA, although not other key mTORC components. Together, our report proposes USP39 as a biomarker and oncogenic factor in ESCC, with a potential for targeting the USP39/mTOR2/Rictor axis as a therapeutic strategy. Furthermore, our study adds ESCC to the list of cancers where USP39 contributes to tumorigenesis and progression.

Abstract 261: Robust Cardioprotection Afforded by a Previously Unrecognized Link between the Unfolded Protein Response and the Hexosamine Biosynthetic Pathway

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Zhao V Wang ◽  
Yingfeng Deng ◽  
Ningguo Gao ◽  
Zully Pedrozo ◽  
Dan Li ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Biosynthetic Pathway ◽  
Ischemia Reperfusion ◽  
Uridine Diphosphate ◽  
Hexosamine Biosynthetic Pathway ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Rate Limiting

Background: The hexosamine biosynthetic pathway (HBP) generates UDP-GlcNAc (uridine diphosphate N-acetylglucosamine) for glycan synthesis and O-linked GlcNAc (O-GlcNAc) protein modifications. Despite the established role of the HBP in glucose metabolism and multiple diseases, regulation of the HBP remains largely undefined. Methods & Results: Here, we show that spliced Xbp1 (Xbp1s), the most conserved signal transducer of the unfolded protein response (UPR), is a direct transcriptional activator of the HBP. We demonstrate that the UPR triggers activation of the HBP by means of Xbp1s-dependent transcription of genes coding for key, rate-limiting enzymes. We establish that this previously unrecognized UPR-HBP axis is triggered in a variety of stress conditions known to promote O-GlcNAc modification. We go on to demonstrate that Xbp1s, acutely stimulated by ischemia/reperfusion (I/R) in heart, confers robust cardioprotection against I/R injury. We also show that HBP induction is required for this cardioprotective response. Mechanistically, HBP may mediate the adaptive branch of the UPR by activating autophagy and ER-associated degradation. Conclusion: These studies reveal that Xbp1s couples the UPR to the HBP, promoting robust cardioprotection during I/R.

scholarly journals Molecular Imaging of Mesothelioma withT99mc-ECG andG68a-ECG

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Yin-Han Zhang ◽  
Jerry Bryant ◽  
Fan-Lin Kong ◽  
Dong-Fang Yu ◽  
Richard Mendez ◽  
...  
Keyword(s):  
Biosynthetic Pathway ◽  
Liquid Ammonia ◽  
Therapeutic Response ◽  
Lung Tumor ◽  
Post Injection ◽  
Tumor Uptake ◽  
Hexosamine Biosynthetic Pathway ◽  
Density Ratios

We have developed ethylenedicysteine-glucosamine (ECG) as an alternative to18F-fluoro-2-deoxy-D-glucose (18F-FDG) for cancer imaging. ECG localizes in the nuclear components of cells via the hexosamine biosynthetic pathway. This study was to evaluate the feasibility of imaging mesothelioma withT99mc-ECG andG68a-ECG. ECG was synthesized from thiazolidine-4-carboxylic acid and 1,3,4,6-tetra-O-acetyl-2-amino-D-glucopyranose, followed by reduction in sodium and liquid ammonia to yield ECG (52%). ECG was chelated withT99mc/tin (II) andG68a/69Ga chloride forin vitroandin vivostudies in mesothelioma. The highest tumor uptake ofT99mc-ECG is 0.47 at 30 min post injection, and declined to 0.08 at 240 min post injection. Tumor uptake (%ID/g), tumor/lung, tumor/blood, and tumor/muscle count density ratios forT99mc-ECG (30–240 min) were0.47±0.06to0.08±0.01;0.71±0.07to0.85±0.04;0.47±0.03to0.51±0.01, and3.49±0.24to5.06±0.25; forG68a-ECG (15–60 min) were0.70±0.06to0.92±0.08;0.64±0.05to1.15±0.08;0.42±0.03to0.67±0.07, and3.84±0.52to7.00±1.42; for18F-FDG (30–180 min) were1.86±0.22to1.38±0.35;3.18±0.44to2.92±0.34,4.19±0.44to19.41±2.05and5.75±2.55to3.33±0.65, respectively. Tumor could be clearly visualized withT99mc-ECG andG68a-ECG in mesothelioma-bearing rats.T99mc-ECG andG68a-ECG showed increased uptake in mesothelioma, suggesting they may be useful in diagnosing mesothelioma and also monitoring therapeutic response.

scholarly journals In vivo and in vitro evidence that chronic activation of the hexosamine biosynthetic pathway interferes with leptin-dependent STAT3 phosphorylation

2015 ◽  
Vol 308 (6) ◽  
pp. R543-R555 ◽  
Author(s):  
Arthur D. Zimmerman ◽  
Ruth B. S. Harris
Keyword(s):  
Biosynthetic Pathway ◽  
Sucrose Solution ◽  
Leptin Resistance ◽  
Cytokine Signaling ◽  
Hexosamine Biosynthetic Pathway ◽  
Stat3 Phosphorylation ◽  
New Evidence ◽  
Stimulation Of

We previously reported that a 2-day peripheral infusion of glucosamine caused leptin resistance in rats, suggesting a role for the hexosamine biosynthetic pathway (HBP) in the development of leptin resistance. Here we tested leptin responsiveness in mice in which HBP activity was stimulated by offering 30% sucrose solution in addition to chow and water or by infusing glucosamine. Mice were leptin resistant after 33 days of access to sucrose. Resistance was associated with increased activity of the HBP and with phosphorylation of transcription factor signal transducer and activator of transcription-3 Tyr705 [pSTAT3(Y705)] but inhibition of suppressor of cytokine signaling 3 in the liver and hypothalamus. Intravenous infusion of glucosamine for 3 h stimulated pSTAT3(Y705) but prevented leptin-induced phosphorylation of STAT3(S727). In an in vitro system, glucose, glucosamine, and leptin each dose dependently increased O-linked β- N-acetylglucosamine ( O-GlcNAc) protein and pSTAT3(Y705) in HepG2 cells. To test the effect of glucose on leptin responsiveness cells were incubated in 5.5 mM (LG) or 20 mM (HG) glucose for 18 h and were treated with 0 or 50 ng/ml leptin for 15 min. HG alone and LG + leptin produced similar increases in O-GlcNAc protein, glutamine fructose-6-phosphate amidotransferase (GFAT), and pSTAT3(Y705) compared with LG media. Leptin did not stimulate these proteins in HG cells, suggesting leptin resistance. Leptin-induced pSTAT3(S727) was prevented by HG media. Inhibition of GFAT with azaserine prevented LG + leptin and HG stimulation of pSTAT3. These data demonstrate development of leptin resistance in sucrose-drinking mice and provide new evidence of leptin-induced stimulation of the HBP.

scholarly journals Hexosamine Biosynthetic Pathway-Derived O-GlcNAcylation Is Critical for RANKL-Mediated Osteoclast Differentiation

2021 ◽  
Vol 22 (16) ◽  
pp. 8888
Author(s):  
Myoung Jun Kim ◽  
Hyuk Soon Kim ◽  
Sangyong Lee ◽  
Keun Young Min ◽  
Wahn Soo Choi ◽  
...  
Keyword(s):  
Biosynthetic Pathway ◽  
Target Therapy ◽  
Osteoclast Differentiation ◽  
Bone Diseases ◽  
Nuclear Factor ◽  
Post Translational Modification ◽  
Activated T Cells ◽  
Hexosamine Biosynthetic Pathway

O-linked-N-acetylglucosaminylation (O-GlcNAcylation) performed by O-GlcNAc transferase (OGT) is a nutrient-responsive post-translational modification (PTM) via the hexosamine biosynthetic pathway (HBP). Various transcription factors (TFs) are O-GlcNAcylated, affecting their activities and significantly contributing to cellular processes ranging from survival to cellular differentiation. Given the pleiotropic functions of O-GlcNAc modification, it has been studied in various fields; however, the role of O-GlcNAcylation during osteoclast differentiation remains to be explored. Kinetic transcriptome analysis during receptor activator of nuclear factor-kappaB (NF-κB) ligand (RANKL)-mediated osteoclast differentiation revealed that the nexus of major nutrient metabolism, HBP was critical for this process. We observed that the critical genes related to HBP activation, including Nagk, Gfpt1, and Ogt, were upregulated, while the global O-GlcNAcylation was increased concomitantly during osteoclast differentiation. The O-GlcNAcylation inhibition by the small-molecule inhibitor OSMI-1 reduced osteoclast differentiation in vitro and in vivo by disrupting the translocation of NF-κB p65 and nuclear factor of activated T cells c1 (NFATc1) into the nucleus by controlling their PTM O-GlcNAcylation. Furthermore, OSMI-1 had a synergistic effect with bone target therapy on osteoclastogenesis. Lastly, knocking down Ogt with shRNA (shOgt) mimicked OSMI-1’s effect on osteoclastogenesis. Targeting O-GlcNAcylation during osteoclast differentiation may be a valuable therapeutic approach for osteoclast-activated bone diseases.

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