Journal
CANCER RESEARCH
Volume 74, Issue 2, Pages 575-585Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-13-1836
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Funding
- Graduate School of Medical Sciences, Kumamoto University, Japan
- Grants-in-Aid for Scientific Research [25462028, 24591966, 25462027] Funding Source: KAKEN
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The transcription factor PPAR-gamma plays various roles in lipid metabolism, inflammation, cellular differentiation, and apoptosis. PPAR-gamma agonists used to treat diabetes may have utility in cancer treatment. Efatutazone is a novel later generation PPAR-gamma agonist that selectively activates PPAR-gamma target genes and has antiproliferative effects in a range of malignancies. In this study, we investigated PPAR-gamma status in esophageal squamous cell carcinoma (ESCC) and investigated the antiproliferative effects of efatutazone. PPAR-gamma was expressed heterogeneously in ESCC, in which it exhibited an inverse relationship with Ki-67 expression. PPAR-gamma expression was associated independently with good prognosis in ESCC. Efatutazone, but not the conventional PPAR-gamma 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. (C)2013 AACR.
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