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

Abstract

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 Apc min/+ 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.axitinib | β-catenin | asymmetric cell division | SHPRH

MYB fusions and CD markers as tools for authentication and purification of cancer stem cells from salivary adenoid cystic carcinoma

“…While exact functions of cis -NAT are not known, they may inhibit expression of corresponding sense transcripts via transcription interference or post-transcriptionally (41). Interestingly, SHPRH functions as a tumor suppressor protein that induces degradation of β-catenin, a CSC driver, and has been recently recognized as a target of axitinib, a small molecule inhibitor of WNT/β-catenin signaling (42). It may be hypothesized therefore that the MYB-RP11-54515.3 fusion may inhibit SHPRH translation and stimulate ACC-CSC via WNT/β-catenin signaling.…”

“…To this end, we used CyTOF, an innovative flow cytometry technology, which is based on time-of-flight mass-spectrometry (43). CyTOF analysis demonstrated that CD133+ AC-CSC are highly enriched with β-catenin and STAT3, two major targets actively explored in novel cancer-targeting therapies (42,44). We and others previously implicated both STAT3 and Wnt/β-catenin signaling in ACC (13,45–47), and this study, for the first time, links both pathways to CSC suggesting their cooperation and providing targets for ACC-CSC eradication.…”

Discovery of chemical probes that suppress Wnt/β‐catenin signaling through high‐throughput screening

“…Recently, another E3 ubiquitin ligase, SHPRH that controls β‐catenin stability, was also found to be targeted by a small molecule compound. Screening of an FDA‐approved drug library using SuperTOPFlash luciferase assay led to the discovery of axitinib, a known inhibitor of multireceptor tyrosine kinases, especially vascular endothelial growth factor receptors, that stabilize SHPRH protein, thereby increasing the degradation of β‐catenin . Another screening of 800 compounds using TOPFlash assay identified CGK062 that promotes protein kinase Cα‐mediated phosphorylation of β‐catenin at Ser33/Ser37 .…”

“…Screening of an FDA-approved drug library using SuperTOPFlash luciferase assay led to the discovery of axitinib, a known inhibitor of multireceptor tyrosine kinases, especially vascular endothelial growth factor receptors, 57 that stabilize SHPRH protein, thereby increasing the degradation of β-catenin. 58 Another screening of 800 compounds using TOPFlash assay identified CGK062 that promotes protein kinase Cα-mediated phosphorylation of β-catenin at Ser33/Ser37. 59 De Robertis et al 60 press the chemically induced eyeless phenotype in zebrafish embryos.…”

Cross-talk between Hippo and Wnt signalling pathways in intestinal crypts: insights from an agent-based model

“…Instead, Wnt is shared stochastically between daughter cells, so that daughter cells contain a proportion 0.5±! of the mother cell's Wnt level at each division (57,58), where ! is a sample from a Normally distributed random variable with zero mean and standard deviation σ (set as a model parameter), appropriately truncated to ensure the proportion remains in the interval [0,1].…”