論文 - 詳細
| RRC ID | 44767 |
|---|---|
| 著者 | Sawayama H, Ishimoto T, Watanabe M, Yoshida N, Sugihara H, Kurashige J, Hirashima K, Iwatsuki M, Baba Y, Oki E, Morita M, Shiose Y, Baba H. |
| タイトル | Small molecule agonists of PPAR-γ exert therapeutic effects in esophageal cancer. |
| ジャーナル | Cancer Res |
| Abstract |
The transcription factor PPAR-γ plays various roles in lipid metabolism, inflammation, cellular differentiation, and apoptosis. PPAR-γ agonists used to treat diabetes may have utility in cancer treatment. Efatutazone is a novel later generation PPAR-γ agonist that selectively activates PPAR-γ target genes and has antiproliferative effects in a range of malignancies. In this study, we investigated PPAR-γ status in esophageal squamous cell carcinoma (ESCC) and investigated the antiproliferative effects of efatutazone. PPAR-γ was expressed heterogeneously in ESCC, in which it exhibited an inverse relationship with Ki-67 expression. PPAR-γ expression was associated independently with good prognosis in ESCC. Efatutazone, but not the conventional PPAR-γ agonist troglitazone, inhibited ESCC cell proliferation in vitro and in vivo. Mechanistic investigations suggested that efatutazone acted by upregulating p21Cip1 protein in the nucleus through inactivation of the Akt pathway and dephosphorylation of p21Cip1 at Thr145 without affecting the transcriptional activity of p21Cip1. We also found that treatment with efatutazone led to phosphorylation of the EGF receptor and activation of the mitogen-activated protein kinase (MAPK) pathway. Accordingly, the combination of efatutazone with the antiepithelial growth factor receptor antibody cetuximab synergized to negatively regulate the phosphoinositide 3-kinase-Akt and MAPK pathways. Together, our results suggest that efatutazone, alone or in combination with cetuximab, may offer therapeutic effects in ESCC. |
| 巻・号 | 74(2) |
| ページ | 575-85 |
| 公開日 | 2014-1-15 |
| DOI | 10.1158/0008-5472.CAN-13-1836 |
| PII | 0008-5472.CAN-13-1836 |
| PMID | 24272485 |
| MeSH | Aged Animals Antibodies, Monoclonal, Humanized / administration & dosage Antineoplastic Agents / pharmacology Carcinoma, Squamous Cell / drug therapy Carcinoma, Squamous Cell / metabolism* Cell Line, Tumor Cell Nucleus / metabolism Cell Proliferation / drug effects Cetuximab Cyclin-Dependent Kinase Inhibitor p21 / metabolism Epithelium / drug effects Esophageal Neoplasms / drug therapy Esophageal Neoplasms / metabolism* Esophageal Squamous Cell Carcinoma Female Gene Expression Regulation, Neoplastic* Humans MAP Kinase Signaling System Male Mice Mice, Nude Middle Aged Neoplasm Transplantation PPAR gamma / agonists* PPAR gamma / metabolism Prognosis Signal Transduction Thiazolidinediones / administration & dosage Thiazolidinediones / pharmacology* Treatment Outcome |
| IF | 9.727 |
| 引用数 | 33 |
| WOS 分野 | ONCOLOGY |
| 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 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 1 |
| 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 | |
| ヒト・動物細胞 | TE-1(RCB1894) TE-14(RCB2101) TE-11(RCB2100) TE-10(RCB2099) TE-4(RCB2097) TE-9(RCB1988) TE-15(RCB1951) TE-6(RCB1950) TE-8(RCB2098) |