Axitinib blocks Wnt/β-catenin signaling and directs asymmetric cell division in cancer

Significance The Wnt (wingless)/β-catenin signaling pathway is an attractive target for cancer therapy. However, known Wnt inhibitors are still far from clinical use. Here we report that the clinically approved drug axitinib strongly inhibits Wnt/β-catenin signaling in vitro and in vivo. In particular, a phenotype of Wnt inhibition called “Wnt asymmetry” was revealed in axitinib-treated cancer cells. The identification of E3 ubiquitin ligase SHPRH (SNF2, histone-linker, PHD and RING finger domain-containing helicase) as the functional target implies that axitinib blocking of Wnt signaling is independent of genetic mutations that are frequently observed in cancer patients. Collectively, our results suggest a mechanism of nuclear β-catenin regulation and highlight axitinib as a promising therapeutic agent for cancer patients with aberrant Wnt/β-catenin signaling. Oncogenic mutations of the Wnt (wingless)/β-catenin pathway are frequently observed in major cancer types. Thus far, however, no therapeutic agent targeting Wnt/β-catenin signaling is available for clinical use. Here we demonstrate that axitinib, a clinically approved drug, strikingly blocks Wnt/β-catenin signaling in cancer cells, zebrafish, and Apcmin/+ mice. Notably, axitinib dramatically induces Wnt asymmetry and nonrandom DNA segregation in cancer cells by promoting nuclear β-catenin degradation independent of the GSK3β (glycogen synthase kinase3β)/APC (adenomatous polyposis coli) complex. Using a DARTS (drug affinity-responsive target stability) assay coupled to 2D-DIGE (2D difference in gel electrophoresis) and mass spectrometry, we have identified the E3 ubiquitin ligase SHPRH (SNF2, histone-linker, PHD and RING finger domain-containing helicase) as the direct target of axitinib in blocking Wnt/β-catenin signaling. Treatment with axitinib stabilizes SHPRH and thereby increases the ubiquitination and degradation of β-catenin. Our findings suggest a previously unreported mechanism of nuclear β-catenin regulation and indicate that axitinib, a clinically approved drug, would provide therapeutic benefits for cancer patients with aberrant nuclear β-catenin activation.

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