title: Small molecule agonists of PPAR-γ exert therapeutic effects in esophageal cancer.
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.
authors.affiliation: Authors' Affiliations: Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto; Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka; and Research and Development Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sawayama
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Ishimoto
authors.forename: Masayuki
authors.initials: M
authors.lastname: Watanabe
authors.forename: Naoya
authors.initials: N
authors.lastname: Yoshida
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Sugihara
authors.forename: Junji
authors.initials: J
authors.lastname: Kurashige
authors.forename: Kotaro
authors.initials: K
authors.lastname: Hirashima
authors.forename: Masaaki
authors.initials: M
authors.lastname: Iwatsuki
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.forename: Eiji
authors.initials: E
authors.lastname: Oki
authors.forename: Masaru
authors.initials: M
authors.lastname: Morita
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Shiose
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
mesh_terms: D000368:Aged; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004848:Epithelium / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011379:Prognosis; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047495:PPAR gamma; D045162:Thiazolidinediones; C510342:efatutazone; D000068818:Cetuximab