Functional Diversity of Mammalian Sialyltransferases

Takashima, Shou; Tsuji, S.

doi:10.4052/tigg.23.178

Cited by 31 publications

(12 citation statements)

References 138 publications

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“…Increased sialylation during cancerous transformation and tumor progression is well documented [43–45] and most likely results from the overexpression of sialyltransferases [45, 46] helping, therefore, tumor cells to withstand apoptosis. Cell and tissue specificity of these enzymes suggests that each type (including probably malignant cells) have a unique “sialome” which may be used to document cell origin or pathology [47].…”

Section: Resultsmentioning

confidence: 99%

Tissue ACE phenotyping in prostate cancer

et al. 2019

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Epithelial cells of prostate express significant level of ACE and, as a result, seminal fluid has 50-fold more ACE than plasma. The substitution of highly specialized prostate epithelial cells by tumor cells results in dramatic decrease in ACE production in prostate tissues. We performed detailed characterization of ACE status in prostate tissues from patients with benign prostate hyperplasia (BPH) and prostate cancer (PC) using new approach- ACE phenotyping, that includes evaluation of: 1) ACE activity with two substrates (HHL and ZPHL); 2) the ratio of the rates of their hydrolysis (ZPHL/HHL ratio); 3) the ratio of immunoreactive ACE protein to ACE activity; 4) the pattern of mAbs binding to different epitopes on ACE – ACE conformational fingerprint - to reveal conformational changes in prostate ACE due to prostate pathology. ACE activity dramatically decreased and the ratio of immunoreactive ACE protein to ACE activity increased in PC tissues. The catalytic parameter, ZPHL/HHL ratio, increased in prostate tissues from all patients with PC, but was did not change for most |BPH patients. Nevertheless, prostate tissues of several patients diagnosed with BPH based on histology, also demonstrated decreased ACE activity and increased immunoreactive ACE protein/ACE activity and ZPHL/HHL ratios, that could be considered as more early indicators of prostate cancer development than routine histology. Thus, ACE phenotyping of prostate biopsies has a potential to be an effective approach for early diagnostics of prostate cancer or at least for differential diagnostics of BPH and PC.

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Section: Resultsmentioning

confidence: 99%

Tissue ACE phenotyping in prostate cancer

et al. 2019

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“…In humans, the ST family is composed of 20 individual members ( 10 – 12 ). These enzymes are expressed in a cell- and tissue-specific manner, proving each cell type with a unique “sialome” ( 13 ).…”

Section: The Sialyltransferase Familymentioning

confidence: 99%

“…Exquisite stereoselectivity results in ST-catalyzed formation of an α-linked sialic acid to a precise hydroxyl group on a specific particular saccharide residue. The combination of the acceptor saccharide residue and the precise hydroxyl group on this residue can be used to divide the family into four distinct families (Figure 1 C) ( 11 , 12 , 14 ). For example, ST6Gal enzymes catalyze the transfer of sialic acid to the 6′-hydroxyl group of a Gal residue, ST3Gal enzymes catalyze the transfer of sialic acid to the 3′-hydroxyl group of a Gal residue, ST3GalNAc enzymes catalyze the transfer of sialic acid to the 6′-hydroxyl group of a GalNAc, and ST3Sia enzymes catalyze the transfer of sialic acid to the 8′-hydroxyl group of another sialic acid residue.…”

Section: The Sialyltransferase Familymentioning

confidence: 99%

Targeting Selectins and Their Ligands in Cancer

2016

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Aberrant glycosylation is a hallmark of cancer cells with increased evidence pointing to a role in tumor progression. In particular, aberrant sialylation of glycoproteins and glycolipids has been linked to increased immune cell evasion, drug evasion, drug resistance, tumor invasiveness, and vascular dissemination, leading to metastases. Hypersialylation of cancer cells is largely the result of overexpression of sialyltransferases (STs). Differentially, humans express twenty different STs in a tissue-specific manner, each of which catalyzes the attachment of sialic acids via different glycosidic linkages (α2-3, α2-6, or α2-8) to the underlying glycan chain. One important mechanism whereby overexpression of STs contributes to an enhanced metastatic phenotype is via the generation of selectin ligands. Selectin ligand function requires the expression of sialyl-Lewis X and its structural isomer sialyl-Lewis A, which are synthesized by the combined action of alpha α1-3-fucosyltransferases, α2-3-sialyltransferases, β1-4-galactosyltranferases, and N-acetyl-β-glucosaminyltransferases. The α2-3-sialyltransferases ST3Gal4 and ST3Gal6 are critical to the generation of functional E- and P-selectin ligands and overexpression of these STs have been linked to increased risk of metastatic disease in solid tumors and poor outcome in multiple myeloma. Thus, targeting selectins and their ligands as well as the enzymes involved in their generation, in particular STs, could be beneficial to many cancer patients. Potential strategies include ST inhibition and the use of selectin antagonists, such as glycomimetic drugs and antibodies. Here, we review ongoing efforts to optimize the potency and selectivity of ST inhibitors, including the potential for targeted delivery approaches, as well as evaluate the potential utility of selectin inhibitors, which are now in early clinical development.

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“…Onе of changes reported for cancer cells is the increase of sialic acid carbohydrates on their cell membrane [58]. Hyperglycosylation as the increase of sialic acids most likely results from the overexpression of sialyltransferases–a broad family of more than 20 different enzymes which have defined tissue-specificity [59]. Cell and tissue specificity of these enzymes allows to assume, that each type (including probably malignant cells) have a unique “sialome” which may be used to document cell origin or pathology [60].…”

Section: Resultsmentioning

confidence: 99%

Tissue ACE phenotyping in lung cancer

et al. 2019

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BackgroundPulmonary vascular endothelium is the main metabolic site for Angiotensin I-Converting Enzyme (ACE)-mediated degradation of several biologically-active peptides (angiotensin I, bradykinin, hemo-regulatory peptide Ac-SDKP). Primary lung cancer growth and lung cancer metastases decrease lung vascularity reflected by dramatic decreases in both lung and serum ACE activity. We performed precise ACE phenotyping in tissues from subjects with lung cancer.MethodologyACE phenotyping included: 1) ACE immunohistochemistry with specific and well-characterized monoclonal antibodies (mAbs) to ACE; 2) ACE activity measurement with two ACE substrates (HHL, ZPHL); 3) calculation of ACE substrates hydrolysis ratio (ZPHL/HHL ratio); 4) the pattern of mAbs binding to 17 different ACE epitopes to detect changes in ACE conformation induced by tumor growth (conformational ACE fingerprint).ResultsACE immunostaining was dramatically decreased in lung cancer tissues confirmed by a 3-fold decrease in ACE activity. The conformational fingerprint of ACE from tumor lung tissues differed from normal lung (6/17 mAbs) and reflected primarily higher ACE sialylation. The increase in ZPHL/HHL ratio in lung cancer tissues was consistent with greater conformational changes of ACE. Limited analysis of the conformational ACE fingerprint in normal lung tissue and lung cancer tissue form the same patient suggested a remote effect of tumor tissue on ACE conformation and/or on “field cancerization” in a morphologically-normal lung tissues.Conclusions/SignificanceLocal conformation of ACE is significantly altered in tumor lung tissues and may be detected by conformational fingerprinting of human ACE.

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Functional Diversity of Mammalian Sialyltransferases

Cited by 31 publications

References 138 publications

Tissue ACE phenotyping in prostate cancer

Tissue ACE phenotyping in prostate cancer

Targeting Selectins and Their Ligands in Cancer

Tissue ACE phenotyping in lung cancer

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