title: Sirtuin 1 promotes the growth and cisplatin resistance of endometrial carcinoma cells: a novel therapeutic target.
abstract: Sirtuin 1 (SIRT1), originally identified as a longevity gene, is induced by caloric restriction, and regulates various cellular functions including DNA repair, cell survival and metabolism via the deacetylation of target proteins such as histone and p53. These functions are considered to act dualistically as preventing or facilitating cancer. This study aimed to clarify the expression and role of SIRT1 in endometrial carcinoma. Because a high-calorie diet was a well-known risk factor for endometrial carcinoma, we first hypothesized that SIRT1 might be downregulated in normal endometrial glandular cells of obese women. However, no correlation was observed between the expression of SIRT1 and body mass index (BMI). In contrast, regardless of BMI, the immunohistochemical expression of SIRT1 was significantly higher in endometrial carcinoma (108 cases) than in normal endometria (60 cases) (P<0.05), and its overexpression was associated with a shorter survival (P<0.05). Our experiments in vivo revealed that SIRT1 accelerated the proliferation of endometrial carcinoma cell lines (HHUA, HEC151, and HEC1B). SIRT1 overexpression significantly enhanced the resistance for cisplatin and paclitaxel in HHUA cells. Although p53 is an important target protein for SIRT1, the selective SIRT1 inhibitor (EX527) significantly suppressed the proliferation and cisplatin resistance of three endometrial carcinoma cell lines regardless of the p53 mutation status. In addition, SIRT1 overexpression in HHUA cells accelerated tumor growth and cisplatin resistance in nude mice, and EX527 significantly suppressed the growth of tumors of HHUA and HEC1B cells. No adverse effect of EX527 was observed in these mice. In conclusion, SIRT1 is involved in the acquisition of the aggressive behavior associated with endometrial carcinoma, and the SIRT1 inhibitor, EX527, may be a useful agent for the treatment of this malignancy.
authors.affiliation: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Asaka
authors.affiliation: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Japan.
authors.forename: Tsutomu
authors.identifier: http://orcid.org/0000-0002-1513-9473
authors.initials: T
authors.lastname: Miyamoto
authors.affiliation: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ando
authors.affiliation: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Japan.
authors.forename: David Hamisi
authors.initials: DH
authors.lastname: Mvunta
authors.affiliation: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Japan.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Kobara
authors.affiliation: Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Japan.
authors.forename: Tanri
authors.initials: T
authors.lastname: Shiozawa
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology / Q000627:therapeutic use*; D018269:Carcinoma, Endometrioid / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002945:Cisplatin; D019008:Drug Resistance, Neoplasm; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D004717:Endometrium / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D002227:Carbazoles; D016159:Tumor Suppressor Protein p53; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D002945:Cisplatin