title: Proliferative and signaling activities of insulin analogues in endometrial cancer cells.
abstract: Insulin analogues have been developed to achieve further improvement in the therapy of diabetes. However, modifications introduced into the insulin molecule may enhance their affinity for the insulin-like growth factor-1 receptor (IGF1R). Hyperinsulinemia has been identified as a risk factor for endometrial cancer. We hypothesized that insulin analogues may elicit atypical proliferative and signaling activities in endometrial cancer cells. Our results demonstrate that glargine, but not detemir, stimulated cell proliferation, displayed an anti-apoptotic effect, and had a positive effect on cell cycle progression in endometrial cancer cell lines ECC-1 and USPC-1. In addition, we showed that glargine and detemir induced dual activation of the insulin receptor (INSR) and IGF1R in both cell types. Furthermore, we showed that glargine elicited signaling events that are markedly different from those induced by insulin. In conclusion, our data support the concept that, although insulin analogues were designed to display insulin-like metabolic effects, glargine and, possibly, additional analogues exhibit IGF1-like activities and, accordingly, may function as IGF1 analogues.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Daniel
authors.initials: D
authors.lastname: Aizen
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Rive
authors.initials: R
authors.lastname: Sarfstein
authors.affiliation: Gynecologic Oncology Unit, Department of Obstetrics and Gynecology, Hillel Yaffe Medical Center, Hadera, Israel.
authors.forename: Ilan
authors.initials: I
authors.lastname: Bruchim
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Doron
authors.initials: D
authors.lastname: Weinstein
authors.affiliation: Endocrine and Diabetes Research Unit, Schneider Children's Medical Center, Petah Tikva 49292, Israel.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Laron
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: hwerner@post.tau.ac.il.
authors.forename: Haim
authors.initials: H
authors.lastname: Werner
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003593:Cytoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D007328:Insulin / Q000031:analogs & derivatives*; D000069036:Insulin Glargine / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007328:Insulin; D000069036:Insulin Glargine; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin
keywords: Endometrial cancer; IGF1 receptor; Insulin; Insulin analogues; Insulin-like growth factor-1 (IGF1)