RRC ID 37931
Author Asaka R, Miyamoto T, Yamada Y, Ando H, Mvunta DH, Kobara H, Shiozawa T.
Title Sirtuin 1 promotes the growth and cisplatin resistance of endometrial carcinoma cells: a novel therapeutic target.
Journal Lab Invest
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.
Volume 95(12)
Pages 1363-73
Published 2015-12-1
DOI 10.1038/labinvest.2015.119
PII labinvest2015119
PMID 26367491
MeSH Animals Carbazoles / pharmacology Carbazoles / therapeutic use* Carcinoma, Endometrioid / drug therapy Carcinoma, Endometrioid / metabolism* Cell Line, Tumor Cell Proliferation Cisplatin* Drug Resistance, Neoplasm* Endometrial Neoplasms / drug therapy Endometrial Neoplasms / metabolism* Endometrium / metabolism Female Humans Immunohistochemistry Mice, Inbred BALB C Mice, Nude Sirtuin 1 / antagonists & inhibitors Sirtuin 1 / metabolism* Stress, Physiological Tumor Suppressor Protein p53 / antagonists & inhibitors Tumor Suppressor Protein p53 / metabolism Xenograft Model Antitumor Assays
IF 4.197
Times Cited 36
Human and Animal Cells HHUA(RCB0658)