論文 - 詳細
| RRC ID | 49679 |
|---|---|
| 著者 | Qu Y, Gharbi N, Yuan X, Olsen JR, Blicher P, Dalhus B, Brokstad KA, Lin B, Øyan AM, Zhang W, Kalland KH, Ke X. |
| タイトル | Axitinib blocks Wnt/β-catenin signaling and directs asymmetric cell division in cancer. |
| ジャーナル | Proc Natl Acad Sci U S A |
| 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. |
| 巻・号 | 113(33) |
| ページ | 9339-44 |
| 公開日 | 2016-8-16 |
| DOI | 10.1073/pnas.1604520113 |
| PII | 1604520113 |
| PMID | 27482107 |
| PMC | PMC4995957 |
| MeSH | Animals Axitinib Cell Division / drug effects* DNA Helicases / physiology Glycogen Synthase Kinase 3 beta / physiology HCT116 Cells Humans Imidazoles / pharmacology* Indazoles / pharmacology* Male Mice Mice, Inbred C57BL Neoplasms / pathology* Protein Kinase Inhibitors / pharmacology* Regeneration / drug effects Ubiquitin-Protein Ligases / physiology Wnt Signaling Pathway / drug effects* Zebrafish beta Catenin / physiology* |
| IF | 9.412 |
| 引用数 | 33 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | News |
| 各媒体での言及数の合計 | 13 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ゼブラフィッシュ | Tg(6xTcf/LefBS-miniP:d2EGFP) |