Suramin enters and accumulates in low pH intracellular compartments of v‐sis‐transformed NIH 3T3 cells

Huang, Shuan Shian; Koh, H. A.; Huang, Jung San

doi:10.1016/s0014-5793(97)01213-1

Cited by 17 publications

(13 citation statements)

References 38 publications

(37 reference statements)

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“…Alternatively, these large, charged molecules might present reduced cell permeability owing to their size or charged residues, and might therefore only interfere with surface PrP. At least for suramin, uptake and intracellular localisation in low pH intracellular compartments (endosomes, lysosomes and TGN) in concentrations similar to those used in our studies have been described (Fransson et al, 1995;Huang et al, 1997). As the majority of the derivatives have similar molecular weights and similar numbers of sulphated substitutions as suramin, a certain cell permeability cannot be excluded.…”

Section: Discussionmentioning

confidence: 69%

Charged bipolar suramin derivatives induce aggregation of the prion protein at the cell surface and inhibit PrPSc replication

Nunziante

Kehler

Maas

et al. 2005

Journal of Cell Science

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The conversion of the cellular prion protein (PrPc) into a pathogenic isoform (PrPSc) is one of the underlying events in the pathogenesis of the fatal transmissible spongiform encephalopathies (TSEs). Numerous compounds have been described to inhibit prion replication and PrPSc accumulation in cell culture. Among these, the drug suramin induces aggregation and re-targeting of PrPc to endocytic compartments. Plasma membrane and sites of conversion into PrPSc are thereby bypassed. In the present study, a library of suramin analogues was tested as a potential class of new anti-prion compounds and the molecular mechanisms underlying these effects were analysed. Treatment of prion-infected neuroblastoma cells with compounds containing symmetrical aromatic sulfonic acid substitutions inhibited de novo synthesis of PrPSc and induced aggregation and reduction of the half-life of PrPc without downregulating PrPc cell surface expression. Half-molecule compounds lacking the symmetrical bipolar structure or the anionic groups had no effect on PrPSc synthesis or PrPc solubility. Cell surface expression of PrPc was necessary for the activity of effective compounds. Suramin derivatives did not induce aggregation of PrPc when transport along the secretory pathway was compromised, suggesting that their effects occur at a post trans-Golgi network (TGN) site, possibly close to the compartment of conversion into PrPSc. In vitro studies with recombinant PrP demonstrated that the inhibitory effect correlated with direct binding to PrP and induction of insoluble PrP aggregates. Our data reveal an anti-prion effect that differs from those characterising other sulphated polyanions and is dependent on the presence of the symmetrical anionic structure of these molecules.

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Section: Discussionmentioning

confidence: 69%

Charged bipolar suramin derivatives induce aggregation of the prion protein at the cell surface and inhibit PrPSc replication

Nunziante

Kehler

Maas

et al. 2005

Journal of Cell Science

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“…Subsequently, Baghdiguian et al (20) performed quantitative auto-radiographic analysis revealing that in the absence of serum albumin labeled suramin was found to enter the human colon adenocarcinoma cells and distribute over the nucleus, the Golgi apparatus, and the mitochondria. In addition, using an indirect acridine orange reporter assay, Huang et al (21) reported that suramin enters and accumulates in low-pH intracellular compartments (endosomes, lysosomes, and transGolgi complex) of normal and v-sis-transformed NIH 3T3 cells. To facilitate the cellular analysis of suramin, we used a serum-starvation protocol developed by Baghdiguian et al (20) to increase the uptake of suramin and treated U2OS cells with this compound in concentrations ranging from 62.5 to 500 μM.…”

Section: Hts Identification Of Suramin As An Inhibitor Of Crl-mediatementioning

confidence: 99%

Suramin inhibits cullin-RING E3 ubiquitin ligases

Chong

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cullin-RING E3 ubiquitin ligases (CRL) control a myriad of biological processes by directing numerous protein substrates for proteasomal degradation. Key to CRL activity is the recruitment of the E2 ubiquitin-conjugating enzyme Cdc34 through electrostatic interactions between E3′s cullin conserved basic canyon and the acidic C terminus of the E2 enzyme. This report demonstrates that a smallmolecule compound, suramin, can inhibit CRL activity by disrupting its ability to recruit Cdc34. Suramin, an antitrypansomal drug that also possesses antitumor activity, was identified here through a fluorescence-based high-throughput screen as an inhibitor of ubiquitination. Suramin was shown to target cullin 1's conserved basic canyon and to block its binding to Cdc34. Suramin inhibits the activity of a variety of CRL complexes containing cullin 2, 3, and 4A. When introduced into cells, suramin induced accumulation of CRL substrates. These observations help develop a strategy of regulating ubiquitination by targeting an E2-E3 interface through small-molecule modulators.protein degradation | K48-polyubiquitination | E3 ligase | E2 enzyme | suramin

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“…Human heparanase shows a strong tendency to localize to perinuclear granules (45). It has been reported that cells take up suramin via caveolae and transport it both to endosomes and the trans-Golgi as well as to the nucleus (46,47). Although degradation of HS by cell surface-located heparanase can be effectively inhibited by suramin (23), recycling Gpc-1 HS is only partially protected from degradation by suramin, because there is also an intracellular NO-dependent degradation (19,20).…”

Section: Suramin Treatment Causes Accumulation Of S-nitrosylatedmentioning

confidence: 99%

Nitric Oxide-dependent Processing of Heparan Sulfate in Recycling S-Nitrosylated Glypican-1 Takes Place in Caveolin-1-containing Endosomes

Cheng

Mani

Born

et al. 2002

Journal of Biological Chemistry

108

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However, such residues were scarce in cell surface glypican-1. Brefeldin A-arrested glypican-1, which was non-S-nitrosylated and carried side chains rich in Nunsubstituted glucosamines, colocalized extensively with caveolin-1 but not with Rab9. Suramin, which inhibits heparanase, induced the appearance of Snitrosylated glypican-1 in caveolin-1-rich compartments. Inhibition of deaminative cleavage did not prevent heparanase from generating heparan sulfate oligosaccharides that colocalized strongly with caveolin-1. Growthquiescent cells displayed extensive NO-dependent deaminative cleavage of heparan sulfate-generating anhydromannose-terminating fragments that were partly associated with acidic vesicles. Proliferating cells generated such fragments during polyamine uptake. We conclude that recycling glypican-1 that is associated with caveolin-1-containing endosomes undergoes sequential N-desulfation/N-deacetylation, heparanase cleavage, S-nitrosylation, NO release, and deaminative cleavage of its side chains in conjunction with polyamine uptake.Mammalian glypican-1 (Gpc-1) 1 is a member of a glycosylphosphatidylinositol (GPI)-linked cell-surface proteoglycan (PG) family with six known members to date. These PG, like other cell surface PG, are selective regulators of ligand-receptor encounters and thereby control growth and development (1-4). Gpc proteins are post-translationally modified by the addition of the glycosaminoglycan heparan sulfate (HS) at sites located close to the C-terminal GPI-membrane anchor (see Scheme 1). The central part of the protein consists of a cysteine-rich domain containing information that ensures a high level of HS substitution (5). Many of the functions of Gpc are dependent on the HS side chains, which are capable of binding and/or activating and/or transporting a variety of growth factors, cytokines, enzymes, viral proteins, and polyamines (6 -11).GPI-anchored proteins are usually associated with sphingolipid-and cholesterol-rich plasma membrane domains. Such enriched domains may exist either as small phase-separated "rafts" or, when associated with caveolin-1 (Cav-1), form flaskshaped plasmalemmal invaginations called caveolae, which are involved in signal transduction and special forms of non-clathrindependent endocytosis mediated by Cav-1-containing endosomes, also called caveosomes (12)(13)(14)(15)(16)(17).Biochemical studies using radioactively labeled precursors have demonstrated recycling of newly made Gpc-1 in normal fibroblasts as well as in transformed cells (18,19). During recycling, the HS side chains are degraded both by heparanase and by NO-dependent deaminative cleavage at N-unsubstituted glucosamine residues (GlcNH 3 ϩ ) (20). New HS chains can then be synthesized on the stubs remaining on the core protein (see Scheme 1). Biosynthesis of HS takes place in the Golgi and involves many interacting enzymes (21,22). The stubs should first be extended with a GlcNAc-hexuronic acid (HexUA) repeat backbone. The GlcNH 3 ϩ residues are either a result of inadequate sulfation dur...

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Suramin enters and accumulates in low pH intracellular compartments of v‐sis‐transformed NIH 3T3 cells

Cited by 17 publications

References 38 publications

Charged bipolar suramin derivatives induce aggregation of the prion protein at the cell surface and inhibit PrPSc replication

Charged bipolar suramin derivatives induce aggregation of the prion protein at the cell surface and inhibit PrPSc replication

Suramin inhibits cullin-RING E3 ubiquitin ligases

Nitric Oxide-dependent Processing of Heparan Sulfate in Recycling S-Nitrosylated Glypican-1 Takes Place in Caveolin-1-containing Endosomes

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