Inhibitor of ppGalNAc-T3-mediated O-glycosylation blocks cancer cell invasiveness and lowers FGF23 levels

Small molecule inhibitors of site-specific O-glycosylation by the polypeptide N-acetylgalactosaminyltransferase (ppGalNAc-T) family are currently unavailable but hold promise as therapeutics, especially if selective against individual ppGalNAc-T isozymes. To identify a compound targeting the ppGalNAc-T3 isozyme, we screened libraries to find compounds that act on a cell-based fluorescence sensor of ppGalNAc-T3 but not on a sensor of ppGalNAc-T2. This identified a hit that subsequent in vitro analysis showed directly binds and inhibits purified ppGalNAc-T3 with no detectable activity against either ppGalNAc-T2 or ppGalNAc-T6. Remarkably, the inhibitor was active in two medically relevant contexts. In cell culture, it opposed increased cancer cell invasiveness driven by upregulated ppGalNAc-T3 suggesting the inhibitor might be anti-metastatic. In cells and mice, it blocked ppGalNAc-T3-mediated glycan-masking of FGF23 thereby increasing its cleavage, a possible treatment of chronic kidney disease. These findings establish a pharmacological approach for the ppGalNAc-transferase family and suggest that targeting specific ppGalNAc-transferases will yield new therapeutics.

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Peyronie's Disease and Mechanotransduction: An In Vitro Analysis of the Cellular Changes to Peyronie's Disease in a Cell‐Culture Strain System

Journal of Sexual Medicine ◽

10.1111/jsm.12082 ◽

2013 ◽

Vol 10 (5) ◽

pp. 1259-1267 ◽

Cited By ~ 21

Author(s):

Eric Chung ◽

Ling De Young ◽

Matthew Solomon ◽

Gerald B. Brock

Keyword(s):

Cell Culture ◽

Peyronie’S Disease ◽

Cellular Changes ◽

A Cell ◽

Peyronie's Disease ◽

Vitro Analysis ◽

In Vitro Analysis

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Self-Assembling Polypeptide Hydrogels as a Platform to Recapitulate the Tumor Microenvironment

Cancers ◽

10.3390/cancers13133286 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3286

Author(s):

Dariusz Lachowski ◽

Carlos Matellan ◽

Ernesto Cortes ◽

Alberto Saiani ◽

Aline F. Miller ◽

...

Keyword(s):

Cell Culture ◽

Tumor Microenvironment ◽

Cancer Cell ◽

Critical Role ◽

Hypoxia Inducible Factor ◽

Pancreatic Cancer Cell Line ◽

Cancer Cell Line ◽

Culture Systems ◽

A Cell

The tumor microenvironment plays a critical role in modulating cancer cell migration, metabolism, and malignancy, thus, highlighting the need to develop in vitro culture systems that can recapitulate its abnormal properties. While a variety of stiffness-tunable biomaterials, reviewed here, have been developed to mimic the rigidity of the tumor extracellular matrix, culture systems that can recapitulate the broader extracellular context of the tumor microenvironment (including pH and temperature) remain comparably unexplored, partially due to the difficulty in independently tuning these parameters. Here, we investigate a self-assembled polypeptide network hydrogel as a cell culture platform and demonstrate that the culture parameters, including the substrate stiffness, extracellular pH and temperature, can be independently controlled. We then use this biomaterial as a cell culture substrate to assess the effect of stiffness, pH and temperature on Suit2 cells, a pancreatic cancer cell line, and demonstrate that these microenvironmental factors can regulate two critical transcription factors in cancer: yes-associated protein 1 (YAP) and hypoxia inducible factor (HIF-1A).

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P2X7 Receptor Promotes Mouse Mammary Cancer Cell Invasiveness and Tumour Progression, and Is a Target for Anticancer Treatment

Cancers ◽

10.3390/cancers12092342 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2342 ◽

Cited By ~ 3

Author(s):

Lucie Brisson ◽

Stéphanie Chadet ◽

Osbaldo Lopez-Charcas ◽

Bilel Jelassi ◽

David Ternant ◽

...

Keyword(s):

Cancer Cells ◽

Cancer Cell ◽

Cancer Progression ◽

P2x7 Receptor ◽

Mammary Cancer ◽

Tumour Progression ◽

Mammary Cancer Cell ◽

Cell Invasiveness ◽

Cancer Cell Invasiveness

The P2X7 receptor is an ATP-gated cation channel with a still ambiguous role in cancer progression, proposed to be either pro- or anti-cancerous, depending on the cancer or cell type in the tumour. Its role in mammary cancer progression is not yet defined. Here, we show that P2X7 receptor is functional in highly aggressive mammary cancer cells, and induces a change in cell morphology with fast F-actin reorganization and formation of filopodia, and promotes cancer cell invasiveness through both 2- and 3-dimensional extracellular matrices in vitro. Furthermore, P2X7 receptor sustains Cdc42 activity and the acquisition of a mesenchymal phenotype. In an immunocompetent mouse mammary cancer model, we reveal that the expression of P2X7 receptor in cancer cells, but not in the host mice, promotes tumour growth and metastasis development, which were reduced by treatment with specific P2X7 antagonists. Our results demonstrate that P2X7 receptor drives mammary tumour progression and represents a pertinent target for mammary cancer treatment.

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