Effects of Metformin on Cellular Proliferation and Steroid Hormone Receptors in Patient-Derived, Low-Grade Endometrial Cancer Cell Lines
| Autor: | Analisa DiFeo, Sam Mesiano, Gretchen Collins |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Steroid hormone receptor medicine.medical_treatment Estrogen receptor Apoptosis 03 medical and health sciences 0302 clinical medicine Cell Line Tumor medicine Humans RNA Messenger Receptor PI3K/AKT/mTOR pathway Aged Cell Proliferation 030219 obstetrics & reproductive medicine Dose-Response Relationship Drug Cell growth Chemistry Estrogen Receptor alpha Obstetrics and Gynecology Metformin Endometrial Neoplasms Steroid hormone 030104 developmental biology Cancer research Female Neoplasm Grading Signal transduction Receptors Progesterone Signal Transduction medicine.drug |
| Zdroj: | Reproductive Sciences. 26:609-618 |
| ISSN: | 1933-7205 1933-7191 |
| DOI: | 10.1177/1933719118779734 |
| Popis: | Endometrial cancer (EC) is the most common gynecologic malignancy and is the result of disruption of the balance between estrogen-stimulated growth and progesterone-induced growth modulation. Metformin has been shown to inhibit EC proliferation; however, its role in early-stage EC and its effects on steroid hormone receptors have not been adequately explored. Our aim was to examine the effects of metformin on cellular proliferation in patient-derived, low-grade EC cell lines and to determine whether it directly modulates steroid hormone receptor expression. Two novel EC cell lines were produced (EM2 and 3) from endometrial tumor tissue obtained from women undergoing surgery. Cellular proliferation was determined by the 3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide assay, and in both cell lines, metformin decreased cell proliferation in a dose-dependent (10-200 µmol/L) manner and induced apoptosis as measured by cleaved PARP. Furthermore, metformin abrogated the effects of E2 on cell proliferation. Using quantitative real-time polymerase chain reaction and Western immunoblotting, metformin significantly decreased estrogen receptor (ER) α messenger RNA abundance but did not consistently affect the expression of progesterone receptor. Estrogen receptor α protein levels significantly decreased across all metformin doses tested, which resulted in a significant decrease in the expression of the ER targets genes Keratin-19 and Wnt-1 inducible signaling pathway 2. In addition, metformin increased phosphorylation of AMPK in a dose-dependent manner (10-200 µmol/L) indicating an effect on mammalian target of rapamycin (mTOR) signaling. Our data suggest that metformin therapy represents a potential fertility-sparing option for women with early-stage EC, given its capacity to inhibit EC cell proliferation, ERα expression, and the mTOR cell proliferation pathway. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink