Article: article from journal or magazin.
Inhibition of Wnt signalling and breast tumour growth by the multi-purpose drug suramin through suppression of heterotrimeric G proteins and Wnt endocytosis.
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
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.
Animals, Antineoplastic Agents/pharmacology, Breast Neoplasms/metabolism, Breast Neoplasms/pathology, Cell Proliferation/drug effects, Endocytosis/drug effects, Female, HEK293 Cells, HeLa Cells, Heterotrimeric GTP-Binding Proteins/metabolism, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Signal Transduction/drug effects, Suramin/pharmacology, Wnt3A Protein/metabolism, Xenograft Model Antitumor Assays
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