title: Genetic screening reveals a link between Wnt signaling and antitubulin drugs.
abstract: The antitubulin drugs, paclitaxel (PX) and colchicine (COL), inhibit cell growth and are therapeutically valuable. PX stabilizes microtubules, while COL promotes their depolymerization. But, the drug concentrations that alter tubulin polymerization are hundreds of times higher than their clinically useful levels. To map genetic targets for drug action at single-gene resolution, we used a human radiation hybrid panel. We identified loci that affected cell survival in the presence of five compounds of medical relevance. For PX and COL, the zinc and ring finger 3 (ZNRF3) gene dominated the genetic landscape at therapeutic concentrations. ZNRF3 encodes an R-spondin regulated receptor that inhibits Wingless/Int (Wnt) signaling. Overexpression of the ZNRF3 gene shielded cells from antitubulin drug action, while small interfering RNA knockdowns resulted in sensitization. Further a potent pharmacological inhibitor of Wnt signaling, Wnt-C59, protected cells from PX and COL. Our results suggest that the antitubulin drugs perturb microtubule dynamics, thereby influencing Wnt signaling.
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Khan
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Bloom
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Faridmoayer
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Smith
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003078:Colchicine / Q000494:pharmacology; D006224:Cricetinae; D006801:Humans; D006822:Hybrid Cells; D017239:Paclitaxel / Q000494:pharmacology; D040641:Quantitative Trait Loci; D015398:Signal Transduction; D050257:Tubulin Modulators / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D050257:Tubulin Modulators; D051153:Wnt Proteins; D044767:Ubiquitin-Protein Ligases; C572950:ZNRF3 protein, human; D017239:Paclitaxel; D003078:Colchicine