PMID- 29848180
OWN - NLM
STAT- MEDLINE
DCOM- 20191223
LR  - 20210816
IS  - 1933-7205 (Electronic)
IS  - 1933-7191 (Linking)
VI  - 26
IP  - 5
DP  - 2019 May
TI  - Effects of Metformin on Cellular Proliferation and Steroid Hormone Receptors in 
      Patient-Derived, Low-Grade Endometrial Cancer Cell Lines.
PG  - 609-618
LID - 10.1177/1933719118779734 [doi]
AB  - 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 micromol/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) alpha messenger RNA abundance but did not consistently affect 
      the expression of progesterone receptor. Estrogen receptor alpha 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 micromol/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, ERalpha 
      expression, and the mTOR cell proliferation pathway.
FAU - Collins, Gretchen
AU  - Collins G
AD  - 1 Department of Reproductive Endocrinology & Infertility, University Hospitals 
      Cleveland Medical Center, Cleveland, OH, USA.
FAU - Mesiano, Sam
AU  - Mesiano S
AD  - 2 Department of Reproductive Biology, Case Western Reserve University, Cleveland, 
      OH, USA.
FAU - DiFeo, Analisa
AU  - DiFeo A
AD  - 3 Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, 
      OH, USA.
LA  - eng
PT  - Journal Article
DEP - 20180530
PL  - United States
TA  - Reprod Sci
JT  - Reproductive sciences (Thousand Oaks, Calif.)
JID - 101291249
RN  - 0 (ESR1 protein, human)
RN  - 0 (Estrogen Receptor alpha)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Progesterone)
RN  - 9100L32L2N (Metformin)
SB  - IM
MH  - Aged
MH  - Apoptosis/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/*drug effects
MH  - Dose-Response Relationship, Drug
MH  - Endometrial Neoplasms/*metabolism
MH  - Estrogen Receptor alpha/*metabolism
MH  - Female
MH  - Humans
MH  - Metformin/*administration & dosage
MH  - Neoplasm Grading
MH  - RNA, Messenger/metabolism
MH  - Receptors, Progesterone/*metabolism
MH  - Signal Transduction/drug effects
OTO - NOTNLM
OT  - endometrial cancer
OT  - metformin
OT  - steroid hormones
EDAT- 2018/06/01 06:00
MHDA- 2019/12/24 06:00
CRDT- 2018/06/01 06:00
PHST- 2018/06/01 06:00 [pubmed]
PHST- 2019/12/24 06:00 [medline]
PHST- 2018/06/01 06:00 [entrez]
AID - 10.1177/1933719118779734 [doi]
PST - ppublish
SO  - Reprod Sci. 2019 May;26(5):609-618. doi: 10.1177/1933719118779734. Epub 2018 May 
      30.