論文 - 詳細
| RRC ID | 44669 |
|---|---|
| 著者 | Jiang Y, Dai J, Zhang H, Sottnik JL, Keller JM, Escott KJ, Sanganee HJ, Yao Z, McCauley LK, Keller ET. |
| タイトル | Activation of the Wnt pathway through AR79, a GSK3β inhibitor, promotes prostate cancer growth in soft tissue and bone. |
| ジャーナル | Mol Cancer Res |
| Abstract |
UNLABELLED:Due to its bone anabolic activity, methods to increase Wnt activity, such as inhibitors of dickkopf-1 and sclerostin, are being clinically explored. Glycogen synthase kinase (GSK3β) inhibits Wnt signaling by inducing β-catenin degradation, and a GSK3β inhibitor, AR79, is being evaluated as an osteoanabolic agent. However, Wnt activation has the potential to promote tumor growth; therefore, the goal of this study was to determine if AR79 has an impact on the progression of prostate cancer. Prostate cancer tumors were established in subcutaneous and bone sites of mice followed by AR79 administration, and tumor growth, β-catenin activation, proliferation, and apoptosis were assessed. Additionally, prostate cancer and osteoblast cell lines were treated with AR79, and β-catenin status, proliferation (with β-catenin knockdown in some cases), and proportion of ALDH(+)CD133(+) stem-like cells were determined. AR79 promoted prostate cancer tumor growth, decreased phospho-β-catenin, increased total and nuclear β-catenin, and increased tumor-induced bone remodeling. Additionally, AR79 treatment decreased caspase-3 and increased Ki67 expression in tumors and increased bone formation in normal mouse tibiae. Similarly, AR79 inhibited β-catenin phosphorylation, increased nuclear β-catenin accumulation in prostate cancer and osteoblast cell lines, and increased proliferation of prostate cancer cells in vitro through β-catenin. Furthermore, AR79 increased the ALDH(+)CD133(+) cancer stem cell-like proportion of the prostate cancer cell lines. In conclusion, AR79, while being bone anabolic, promotes prostate cancer cell growth through Wnt pathway activation. IMPLICATIONS:These data suggest that clinical application of pharmaceuticals that promote Wnt pathway activation should be used with caution as they may enhance tumor growth. |
| 巻・号 | 11(12) |
| ページ | 1597-610 |
| 公開日 | 2013-12-1 |
| DOI | 10.1158/1541-7786.MCR-13-0332-T |
| PII | 1541-7786.MCR-13-0332-T |
| PMID | 24088787 |
| PMC | PMC3869871 |
| MeSH | Anabolic Agents / pharmacology* Animals Bone Neoplasms / metabolism Bone Neoplasms / pathology Bone Neoplasms / secondary* Cell Line, Tumor Glycogen Synthase Kinase 3 / antagonists & inhibitors* Glycogen Synthase Kinase 3 beta Humans Male Mice Mice, Inbred NOD Mice, SCID Neoplasms, Experimental Phosphorylation Prostatic Neoplasms / metabolism Prostatic Neoplasms / pathology* Protein Kinase Inhibitors / pharmacology* Soft Tissue Neoplasms / metabolism Soft Tissue Neoplasms / pathology Soft Tissue Neoplasms / secondary* Tibia Wnt Signaling Pathway / drug effects* Wnt Signaling Pathway / genetics beta Catenin / metabolism |
| IF | 4.63 |
| 引用数 | 22 |
| WOS 分野 | ONCOLOGY CELL BIOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | ST2(RCB0224) |