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

ABSTRACT: Oncogenic mutations of the Wnt (wingless)/?-catenin pathway are frequently observed in major cancer types. Thus far, however, no therapeutic agent targeting Wnt/?-catenin signaling is available for clinical use. Here we demonstrate that axitinib, a clinically approved drug, strikingly blocks Wnt/?-catenin signaling in cancer cells, zebrafish, and Apc(min/+) mice. Notably, axitinib dramatically induces Wnt asymmetry and nonrandom DNA segregation in cancer cells by promoting nuclear ?-catenin degradation independent of the GSK3? (glycogen synthase kinase3?)/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/?-catenin signaling. Treatment with axitinib stabilizes SHPRH and thereby increases the ubiquitination and degradation of ?-catenin. Our findings suggest a previously unreported mechanism of nuclear ?-catenin regulation and indicate that axitinib, a clinically approved drug, would provide therapeutic benefits for cancer patients with aberrant nuclear ?-catenin activation.

SUBMITTER: Qu Y 

PROVIDER: S-EPMC4995957 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature