title: Inhibition of Wnt signalling and breast tumour growth by the multi-purpose drug suramin through suppression of heterotrimeric G proteins and Wnt endocytosis.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne 1011, Switzerland alexey.koval@unil.ch vladimir.katanaev@unil.ch.
authors.forename: Alexey
authors.initials: A
authors.lastname: Koval
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne 1011, Switzerland.
authors.forename: Kamal
authors.initials: K
authors.lastname: Ahmed
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne 1011, Switzerland School of Biomedicine, Far Eastern Federal University, Vladivostok 690950, Russian Federation alexey.koval@unil.ch vladimir.katanaev@unil.ch.
authors.forename: Vladimir L
authors.initials: VL
authors.lastname: Katanaev
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D004705:Endocytosis / Q000187:drug effects*; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015398:Signal Transduction / Q000187:drug effects*; D013498:Suramin / Q000494:pharmacology*; D060509:Wnt3A Protein / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D060509:Wnt3A Protein; D013498:Suramin; D020962:Heterotrimeric GTP-Binding Proteins
keywords: Wnt pathway; drug repositioning; internalization; nucleotide analogue; triple-negative breast cancer