| RRC ID |
44767
|
| Author |
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.
|
| Title |
Small molecule agonists of PPAR-γ exert therapeutic effects in esophageal cancer.
|
| Journal |
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.
|
| Volume |
74(2)
|
| Pages |
575-85
|
| Published |
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
|
| Times Cited |
33
|
|
WOS Category
|
ONCOLOGY
|
| Resource |
| Human and Animal Cells |
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) |
