Sulfonation, an underexploited area: from skeletal development to infectious diseases and cancer

Leung, Ada W.Y.; Backstrom, Ian; Bally, Marcel B.

doi:10.18632/oncotarget.10046

Cited by 46 publications

(45 citation statements)

References 159 publications

(209 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3). This is consistent with our previous studies showing that PAPSS1 knockdown alone affects long-term cancer cell viability (6,25), an effect that is not reflected in short-term cytotoxicity assays performed with monolayer cultures. Although PAPSS1-silenced cells consistently formed spheroids, it is possible that the spheroids formed were not exactly the same as those formed from the nonsilencing controls.…”

Section: Discussionsupporting

confidence: 93%

“…Although the importance of PAPSS enzymes in human physiology is becoming more apparent in recent years, the role of sulfonation in cancer and other human diseases is still poorly understood, particularly in the context of sulfonation reactions within the nucleus that rely on PAPSS1, the nuclear isoform (24)(25)(26). Bruce and colleagues have uncovered PAPSS1 as a novel target for HIV infections and have speculated that sulfonation may play a role in epigenetic modifications of DNA in the nucleus (27).…”

Section: Discussionmentioning

confidence: 99%

“…The combination of PAPSS1 inhibition with these treatment agents resulted in greater accumulation of DNA damage that ultimately lead to cell death, suggesting that sulfonation might be involved directly or indirectly with the recognition of DNA damage or DNA damage repair. It is important to note that the potentiation effects of PAPSS1 suppression on cisplatin and carboplatin activity have also been validated in several ovarian cancer cell lines using colony formation assay, suggesting that the potential for PAPSS1 to be a therapeutic target is not limited to NSCLC (25).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

In Vivo Validation of PAPSS1 (3′-phosphoadenosine 5′-phosphosulfate synthase 1) as a Cisplatin-sensitizing Therapeutic Target

Leung

Veinotte

Melong

et al. 2017

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Our previous screening efforts found that inhibition of PAPSS1 increases the potency of DNA-damaging agents in non-small cell lung cancer (NSCLC) cell lines. Here, we explored the clinical relevance of PAPSS1 and further investigated it as a therapeutic target in preclinical model systems. PAPSS1 expression and cisplatin IC values were assessed in 52 lung adenocarcinoma cell lines. Effects of PAPSS1 inhibition on A549 cisplatin sensitivity under hypoxic and starvation conditions, in 3D spheroids, as well as in zebrafish and mouse xenografts, were evaluated. Finally, the association between PAPSS1 expression levels and survival in patients treated with standard chemotherapy was assessed. Our results show a positive correlation between low PAPSS1 expression and increased cisplatin sensitivity in lung adenocarcinoma. , the potentiation effect was greatest when A549 cells were serum-starved under hypoxic conditions. When treated with low-dose cisplatin, PAPSS1-deficient A549 spheroids showed a 58% reduction in size compared with control cells., PAPSS1 suppression and low-dose cisplatin treatment inhibited proliferation of lung tumor cells in zebrafish xenografts and significantly delayed development of subcutaneous tumors in mice. Clinical data suggest that NSCLC and ovarian cancer patients with low PAPSS1 expression survive longer following platinum-based chemotherapy. These results suggest that PAPSS1 inhibition enhances cisplatin activity in multiple preclinical model systems and that low PAPSS1 expression may serve as a biomarker for platin sensitivity in cancer patients. Developing strategies to target PAPSS1 activity in conjunction with platinum-based chemotherapy may offer an approach to improving treatment outcomes. .

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

In Vivo Validation of PAPSS1 (3′-phosphoadenosine 5′-phosphosulfate synthase 1) as a Cisplatin-sensitizing Therapeutic Target

Leung

Veinotte

Melong

et al. 2017

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…The post-translational covalent modification of biomolecules through the addition of a sulfonyl group (SO3 -) to a hydroxyl or amino acceptor moiety is of importance in a very broad range of biological processes. 1,2 The ubiquitous donor of activated sulfate is 3ʹ-phosphoadenosine 5ʹ-phosphosulfate (PAPS). Sulfation (also termed sulfonation) is catalysed by enzymes called sulfotransferases (STs) which are separated into two general classes.…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Design of Nucleoside-Derived Analogues as Sulfotransferase Inhibitors

Kershaw¹,

Byrne²,

Parsons³

et al. 2019

Preprint

View full text Add to dashboard Cite

Sulfotransferases (STs) catalyse the transfer of a sulfonyl group (‘sulfation’) from the enzyme co-factor 3ʹ-phosphoadenosine 5ʹ-phosphosulfate (PAPS) to a variety of biomolecules. Tyrosine sulfation of proteins and carbohydrate sulfation play a crucial role in many protein-protein interactions and cell signalling pathways in the extracellular matrix. This is catalysed by several membrane-bound STs, including tyrosylprotein sulfotransferase 1 (TPST1) and heparan sulfate 2-O-sulfotransferase (HS2ST1). Recently, involvement of these enzymes and their post-translational modifications in a growing number of disease areas has been reported, including inflammation, cancer and Alzheimer’s disease. Despite their growing importance, the development of small molecules to probe the biological effect of TPST and carbohydrate ST inhibition remains in its infancy. We have used a structure-based approach and molecular docking to design a library of adenosine 3',5'-diphosphate (PAP) and PAPS mimetics based upon 2'-deoxyadenosine and using 2'-deoxy-PAP as a benchmark. The use of allyl groups as masked methyl esters was exploited in the synthesis of PAP-mimetics, and click chemistry was employed for the divergent synthesis of a series of PAPS-mimetics. A suite of in vitro assays employing TPST1 and HS2ST, and a kinase counter screen, were used to evaluate inhibitory parameters and relative specificity for the STs.

show abstract

“…Biological sulphation is a widespread reversible covalent modification found throughout nature [1]. The regulated sulphation of saccharides is critical for cellular signalling, including regulatory interactions between extracellular glycoproteins that control signal transduction and high-affinity interactions between different cellular surfaces [2].…”

Section: Introductionmentioning

confidence: 99%

New tools for carbohydrate sulphation analysis: Heparan Sulphate 2-O-sulphotranserase (HS2ST) is a target for small molecule protein kinase inhibitors

Byrne

Ramakrishnan

et al. 2018

Preprint

View full text Add to dashboard Cite

Sulphation of carbohydrate residues occurs on a variety of glycans destined for secretion, and this modification is essential for efficient matrix-based signal transduction. Heparan sulphate (HS) glycosaminoglycans control physiological functions ranging from blood coagulation to cell proliferation. HS biosynthesis involves membrane-bound Golgi sulphotransferases, including heparan sulphate 2-O-sulphotransferase (HS2ST), which transfers sulphate from the co-factor PAPS (3’-phosphoadenosine 5’-phosphosulphate) to the 2-O position of α-L-iduronate in the maturing oligosaccharide chain. The current lack of simple non-radioactive enzyme assays that can be used to quantify the levels of carbohydrate sulphation hampers kinetic analysis of this process and the discovery of HS2ST inhibitors. In this paper, we describe a new procedure for thermal shift analysis of purified HS2ST. Using this approach, we quantify HS2ST-catalyzed oligosaccharide sulphation using a novel synthetic fluorescent substrate and screen the Published Kinase Inhibitor Set (PKIS), to evaluate compounds that inhibit catalysis. We report the susceptibility of HS2ST to a variety of cell permeable compounds in vitro, including polyanionic polar molecules, the protein kinase inhibitor rottlerin and oxindole-based RAF kinase inhibitors. In a related study, published back-to-back with this article, we demonstrate that Tyrosyl Protein Sulpho Tranferases (TPSTs) are also inhibited by a variety of protein kinase inhibitors. We propose that appropriately validated small molecule compounds could become new tools for rapid inhibition of glycan (and protein) sulphation in cells, and that protein kinase inhibitors might be repurposed or redesigned for the specific inhibition of HS2ST.SUMMARY STATEMENTWe report that HS2ST, which is a PAPS-dependent glycan sulphotransferase, can be assayed using a variety of novel biochemical procedures, including a non-radioactive enzyme-based assay that detects glycan substrate sulphation in real time. HS2ST activity can be inhibited by different classes of compounds, including known protein kinase inhibitors, suggesting new approaches to evaluate the roles of HS2ST-dependent sulphation with small molecules in cells.

show abstract

Sulfonation, an underexploited area: from skeletal development to infectious diseases and cancer

Cited by 46 publications

References 159 publications

In Vivo Validation of PAPSS1 (3′-phosphoadenosine 5′-phosphosulfate synthase 1) as a Cisplatin-sensitizing Therapeutic Target

In Vivo Validation of PAPSS1 (3′-phosphoadenosine 5′-phosphosulfate synthase 1) as a Cisplatin-sensitizing Therapeutic Target

Structure-Based Design of Nucleoside-Derived Analogues as Sulfotransferase Inhibitors

New tools for carbohydrate sulphation analysis: Heparan Sulphate 2-O-sulphotranserase (HS2ST) is a target for small molecule protein kinase inhibitors

Contact Info

Product

Resources

About