Inhibition of Wnt signalling and breast tumour growth by the multi-purpose drug suramin through suppression of heterotrimeric G proteins and Wnt endocytosis
| Autor: | Vladimir L. Katanaev, Alexey Koval, Kamal Ahmed |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Suramin Endocytic cycle Antineoplastic Agents Breast Neoplasms Mice SCID Biology Biochemistry Mice 03 medical and health sciences Mice Inbred NOD Wnt3A Protein Heterotrimeric G protein medicine Animals Humans ddc:612 Molecular Biology Cell Proliferation Wnt signaling pathway LRP6 LRP5 Cell Biology Heterotrimeric GTP-Binding Proteins Xenograft Model Antitumor Assays Endocytosis Drug repositioning HEK293 Cells 030104 developmental biology Antineoplastic Agents/pharmacology Breast Neoplasms/metabolism Breast Neoplasms/pathology Cell Proliferation/drug effects Endocytosis/drug effects Female HeLa Cells Heterotrimeric GTP-Binding Proteins/metabolism Signal Transduction/drug effects Suramin/pharmacology Wnt3A Protein/metabolism Immunology Cancer research Signal Transduction medicine.drug |
| Zdroj: | Biochemical Journal, Vol. 473, No 4 (2016) pp. 371-381 Biochemical Journal, vol. 473, no. 4, pp. 371-381 |
| ISSN: | 1470-8728 0264-6021 |
| DOI: | 10.1042/bj20150913 |
| Popis: | Overactivation of the Wnt signalling pathway underlies oncogenic transformation and proliferation in many cancers, including the triple-negative breast cancer (TNBC), the deadliest form of tumour in the breast, taking about a quarter of a million lives annually worldwide. No clinically approved targeted therapies attacking Wnt signalling currently exist. Repositioning of approved drugs is a promising approach in drug discovery. In the present study we show that a multi-purpose drug suramin inhibits Wnt signalling and proliferation of TNBC cells in vitro and in mouse models, inhibiting a component in the upper levels of the pathway. Through a set of investigations we identify heterotrimeric G proteins and regulation of Wnt endocytosis as the likely target of suramin in this pathway. G protein-dependent endocytosis of plasma membrane-located components of the Wnt pathway was previously shown to be important for amplification of the signal in this cascade. Our data identify endocytic regulation within Wnt signalling as a promising target for anti-Wnt and anti-cancer drug discovery. Suramin, as the first example of such drug or its analogues might pave the way for the appearance of first-in-class targeted therapies against TNBC and other Wnt-dependent cancers. |
| Databáze: | OpenAIRE |
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