Sulfated Polysaccharides from Macroalgae Are Potent Dual Inhibitors of Human ATP-Hydrolyzing Ectonucleotidases NPP1 and CD39

Lopez, Vittoria; Schäkel, Laura; Schuh, Harald; Schmidt, Michael; Mirza, Salahuddin; Renn, Christian; Pelletier, Julie; Lee, Sang-Yong; Sévigny, Jean; Alban, Susanne; Bendas, Gerd; Müller, Christian

doi:10.3390/md19020051

Cited by 9 publications

(14 citation statements)

References 56 publications

(100 reference statements)

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“…A recent study shows that CD40 as well as IL-6 has double targeted synergistic immunotherapy for GBM [46]. Also, ENTPD1(CD39) have reported related to glioma immunotherapy recently [47]. In addition, LAG3 was recognized as checkpoint molecules in GBM immunotherapy [47].The rest genes have not been reported yet.…”

Section: Discussionmentioning

confidence: 99%

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Comprehensive analysis reveals RANBP17 as a potential biomarker for prognosis and immunotherapy in glioblastoma

Tang¹,

Liu

Li³

et al. 2023

Preprint

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Objective: RAN binding protein 17 (RANBP17) gene is a member of the nuclear transport receptor imoprtin family, and have a close relation to the tumorigenesis. However, the role and mechanism of RANBP17 in glioblastoma (GBM) remains unclear. Here, we comprehensively explored the expression, prognostic value, epigenetic modification, immune filtration, tumor stemness, tumor heterogeneity, upstream miRNA and biological function of RANBP17 in GBM combined bioinformatics analysis with functional experiments in vitro. Methods: The expression of RANBP17 mRNA in GBM was analyzed by TIMER, UALCAN and CCGA databases. The prognostic value of RANBP17 was conducted by LinkedOmics, PrognoScan, and CGGA databases. Mutation status and type of RANBP17 was investigated by cBioportal database and COSMIC database, respectively. The RNA modification and DNA methylation of RANBP17 were analyzed by SangerBox and MethSurv databases. The relationships between RANBP17 expression and tumor heterogeneity, tumor stemness, and tumor immunity in human cancers were analyzed via the SangerBox, TISIDB and TIMER databases. Genes related to RANBP17 were screened by Linkedomics database, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were analyzed by DAVID and STRING database, and the protein-protein interaction (PPI) network was constructed by Cytoscape software. Furthermore, miRWalk, ENCORI and miRDB database was used to predict upstream miRNA of RANBP17. Moreover, the counting kit 8 (CCK-8) assay, flow cytometry, and transwell assays were conducted to evaluate the impact of RANBP17 on the proliferation, apoptosis, migration and invasion in U251 cell. Results: The expression of RANBP17 was downregulated and related to IDH mutation status, MGMT methylation status and 1p19q codeletion in GBM, which was associated with poor prognosis. RANBP17 was closely related to mRNA methylation genes, tumor heterogeneity and tumor stemness. GO and KEGG enrichment analysis indicated that RANBP17 was involved in neutrophil degranulation, response to estradiol and inflammatory response. Furthermore, the expression of RANBP17 was negatively correlated with B cell, CD4+ T cell, Macrophage, Neutrophil and dendritic cell, and positively correlated with tumor purity and CD8+ T cell. RANBP17 was also associated with hsa-miR-650, hsa-miR-361-5p, hsa-miR-421, hsa-miR-9-5p, hsa-miR-3612, hsa-miR-299-5p, hsa-miR-2115-3p and hsa-miR-19b-3p. Moreover, cell functional experiments in vitro demonstrated that overexpression of RANBP17 decreased cell proliferation, migration, invasion and facilitated apoptosis in GBM. Conclusions: These findings revealed that RANBP17 was anticipated to be a promising prognostic and immunotherapeutic biomarker in GBM.

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Section: Discussionmentioning

confidence: 99%

“…Also, ENTPD1(CD39) have reported related to glioma immunotherapy recently [47]. In addition, LAG3 was recognized as checkpoint molecules in GBM immunotherapy [47].The rest genes have not been reported yet. The expression level of these genes and RANBP17 and their role in immunotherapy of GBM deserve further discussion.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis reveals RANBP17 as a potential biomarker for prognosis and immunotherapy in glioblastoma

Tang¹,

Liu

Li³

et al. 2023

Preprint

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“…Polysulfated polysaccharides have been revealed to inhibit multiple classes of ecto-ATPases. The endogenous polysulfated polysaccharide heparan sulfate inhibits multiple families of ectoATPases, thus attenuating the degradation of ATP [11,12].. Therefore, we hypothesized that increasing heparan sulfate in the microenvironment of triple-negative cancer cells using heparanase inhibitors would enhance eATP concentrations in the pericellular environment of chemotherapy-treated TNBC cells and hence, augment chemotherapy-induced cell death.…”

Section: Discussionmentioning

confidence: 99%

The role of heparan sulfate in enhancing the chemotherapeutic response in triple-negative breast cancer

Manouchehri,

Marcho,

Cherian

2023

Preprint

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BackgroundAmong women worldwide, breast cancer has the highest incidence and is the leading cause of cancer-related death. Patients with the triple-negative breast cancer (TNBC) subtype have an inferior prognosis in comparison to other breast cancers because current therapies do not facilitate long-lasting responses. Thus, there is a demand for more innovative therapies that induce durable responses.In our previous research, we discovered that augmenting the concentration of extracellular ATP (eATP) greatly enhances the chemotherapeutic response of TNBC cell lines by activating purinergic receptors (P2RXs), leading to cell death through the induction of non-selective membrane permeability. However, eATP levels are limited by several classes of extracellular ATPases. One endogenous molecule of interest that can inhibit multiple classes of extracellular ATPases is heparan sulfate. Polysulfated polysaccharide heparan sulfate itself is degraded by heparanase, an enzyme that is known to be highly expressed in various cancers, including breast cancer. Heparan sulfate has previously been shown to regulate several cancer-related processes such as fibroblast growth factor signaling, neoangiogenesis by sequestering vascular endothelial growth factors in the extracellular matrix, hedgehog signaling and cell adhesion. In this project, we identified an additional mechanism for a tumor suppressor role of heparan sulfate: inhibition of extracellular ATPases, leading to augmented levels of eATP.Several heparanase inhibitors have been previously identified, including OGT 2115, suramin, PI-88, and PG 545. We hypothesized that heparanase inhibitors would augment eATP concentrations in TNBC by increasing heparan sulfate in the tumor microenvironment, resulting in enhanced cell death in response to chemotherapy.MethodsWe treated TNBC cell lines MDA-MB 231, Hs 578t, and MDA-MB 468 and non-tumorigenic immortal mammary epithelial MCF-10A cells with increasing concentrations of the chemotherapeutic agent paclitaxel in the presence of heparan sulfate and/or the heparanase inhibitor OGT 2115 while analyzing eATP release and cell viability. Moreover, to verify that the effects of OGT 2115 are mediated through eATP, we applied specific antagonists to the purinergic receptors P2RX4 and P2RX7. In addition, the protein expression of heparanase was compared in the cell lines by Western blot analysis. We also evaluated the consequences of this therapeutic strategy on the breast cancer-initiating cell population in the treated cells using flow cytometry and tumorsphere formation efficiency assays.ResultsHeparanase was found to be highly expressed in immortal mammary epithelial cells in comparison to TNBC cell lines. The heparanase inhibitor OGT 2115 augmented chemotherapy-induced TNBC cell death and eATP release.ConclusionThese results demonstrate that inhibiting the degradation of heparan sulfate in the tumor microenvironment augments the susceptibility of TNBC cell lines to chemotherapy by increasing extracellular ATP concentrations. This strategy could potentially be applied to induce more enhanced and enduring responses in TNBC patients.

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“…The quantitative analy-sis of the reaction product AMP was performed by CE (AB Sciex, Framingham, USA), according to a published procedure. 56 …”

Section: Methodsmentioning

confidence: 99%

Protein kinase inhibitor ceritinib blocks ectonucleotidase CD39 – a promising target for cancer immunotherapy

Schäkel

Mirza

Winzer

et al. 2022

J Immunother Cancer

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BackgroundAn important mechanism, by which cancer cells achieve immune escape, is the release of extracellular adenosine into their microenvironment. Adenosine activates adenosine A2A and A2B receptors on immune cells constituting one of the strongest immunosuppressive mediators. In addition, extracellular adenosine promotes angiogenesis, tumor cell proliferation, and metastasis. Cancer cells upregulate ectonucleotidases, most importantly CD39 and CD73, which catalyze the hydrolysis of extracellular ATP to AMP (CD39) and further to adenosine (CD73). Inhibition of CD39 is thus expected to be an effective strategy for the (immuno)therapy of cancer. However, suitable small molecule inhibitors for CD39 are not available. Our aim was to identify drug-like CD39 inhibitors and evaluate them in vitro.MethodsWe pursued a repurposing approach by screening a self-compiled collection of approved, mostly ATP-competitive protein kinase inhibitors, on human CD39. The best hit compound was further characterized and evaluated in various orthogonal assays and enzyme preparations, and on human immune and cancer cells.ResultsThe tyrosine kinase inhibitor ceritinib, a potent anticancer drug used for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer, was found to strongly inhibit CD39 showing selectivity versus other ectonucleotidases. The drug displays a non-competitive, allosteric mechanism of CD39 inhibition exhibiting potency in the low micromolar range, which is independent of substrate (ATP) concentration. We could show that ceritinib inhibits ATP dephosphorylation in peripheral blood mononuclear cells in a dose-dependent manner, resulting in a significant increase in ATP concentrations and preventing adenosine formation from ATP. Importantly, ceritinib (1–10 µM) substantially inhibited ATP hydrolysis in triple negative breast cancer and melanoma cells with high native expression of CD39.ConclusionsCD39 inhibition might contribute to the effects of the powerful anticancer drug ceritinib. Ceritinib is a novel CD39 inhibitor with high metabolic stability and optimized physicochemical properties; according to our knowledge, it is the first brain-permeant CD39 inhibitor. Our discovery will provide the basis (i) to develop more potent and balanced dual CD39/ALK inhibitors, and (ii) to optimize the ceritinib scaffold towards interaction with CD39 to obtain potent and selective drug-like CD39 inhibitors for future in vivo studies.

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Sulfated Polysaccharides from Macroalgae Are Potent Dual Inhibitors of Human ATP-Hydrolyzing Ectonucleotidases NPP1 and CD39

Cited by 9 publications

References 56 publications

Comprehensive analysis reveals RANBP17 as a potential biomarker for prognosis and immunotherapy in glioblastoma

Comprehensive analysis reveals RANBP17 as a potential biomarker for prognosis and immunotherapy in glioblastoma

The role of heparan sulfate in enhancing the chemotherapeutic response in triple-negative breast cancer

Protein kinase inhibitor ceritinib blocks ectonucleotidase CD39 – a promising target for cancer immunotherapy

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