title: Ciglitazone enhances ovarian cancer cell death via inhibition of glucose transporter-1.
abstract: Ciglitazone is a peroxisome proliferator-activated receptor γ (PPARγ) agonist and improves insulin sensitivity. Apart from antidiabetic activity, ciglitazone elicits inhibitory effects on cancer cell growth. Recent studies indicate that glucose metabolism plays a key role in malignant diseases. Significant increase in glucose consumption is found under malignant conditions. The role of ciglitazone in cancer cell death in relation to glucose metabolism is unclear. Thus we designed this study to determine the effect of ciglitazone on glucose metabolism. First, we found ciglitazone inhibited glucose uptake in ovarian cancer cells but did not affect hexokinase activity. Ciglitazone decreased expression levels of glucose transporter-1 (GLUT-1). We also found that ciglitazone and siGLUT-1 treatments induced cell death in ovarian cancer cells. We identified that ciglitazone decreased expressions of specific protein 1 (Sp-1) and β-catenin while increased phosphorylation levels of AMP-activated protein kinase. In vivo study using NOD-scid IL2Rgamma(null) mice confirmed that ciglitazone significantly decreased ovarian cancer mass transplanted onto the back of the mice. Finally, we determined GLUT-1 expressions in patients with serous type ovarian cancer and found that GLUT-1 expression was markedly increased in cancer patients and expression level was proportional to the degree of cancer stages. These results suggest that ciglitazone induces apoptosis in ovarian cancer cells by the inhibition of GLUT-1 and provides a possible therapeutic effect of ciglitazone as an adjuvant drug in the treatment of ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Keimyung University, Daegu 704-701, Republic of Korea.
authors.forename: So Jin
authors.initials: SJ
authors.lastname: Shin
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, School of Medicine, Keimyung University, Daegu 704-701, Republic of Korea; Pain Research Center, School of Medicine, Keimyung University, Daegu 704-701, Republic of Korea.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Pathology, School of Medicine, Keimyung University, Daegu 704-701, Republic of Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Kwon
authors.affiliation: Department of Biochemistry, School of Medicine, Keimyung University, Daegu 704-701, Republic of Korea.
authors.forename: Kyo-Cheol
authors.initials: KC
authors.lastname: Mun
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Keimyung University, Daegu 704-701, Republic of Korea. Electronic address: c0035@dsmc.or.kr.
authors.forename: Chi Heum
authors.initials: CH
authors.lastname: Cho
authors.affiliation: Pain Research Center, School of Medicine, Keimyung University, Daegu 704-701, Republic of Korea; Department of Biochemistry, School of Medicine, Keimyung University, Daegu 704-701, Republic of Korea. Electronic address: eyha@dsmc.or.kr.
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Ha
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D005260:Female; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051272:Glucose Transporter Type 1; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D051176:beta Catenin; D055372:AMP-Activated Protein Kinases; C039671:ciglitazone
keywords: Cell death; Ciglitazone; Glucose transporter-1; Ovarian cancer