PMID- 36322951
OWN - NLM
STAT- MEDLINE
DCOM- 20230206
LR  - 20230206
IS  - 1205-7541 (Electronic)
IS  - 0008-4212 (Linking)
VI  - 101
IP  - 1
DP  - 2023 Jan 1
TI  - Therapeutic metformin concentrations positively regulate proliferation in 
      endometrial epithelial cells via mTOR activation and augmented mitochondrial 
      strength.
PG  - 52-64
LID - 10.1139/cjpp-2022-0307 [doi]
AB  - Metformin, an antidiabetic drug, has recently been repositioned in the treatment 
      of several nondiabetic disorders, including reproductive disorders such as 
      polycystic ovarian syndrome, where it improves endometrial functions. In vitro 
      studies employing supratherapeutic concentrations (5-20 mmol/L) of metformin have 
      reported antiproliferative effects on endometrial epithelial and stromal cells. 
      However, animal and human studies have revealed that therapeutic serum 
      concentrations of metformin range between 20 and 70 micromol/L. In the present study, 
      the effect of therapeutic concentrations of metformin was studied on endometrial 
      epithelial cells (EECs). Therapeutic concentrations of metformin induced 
      proliferation in Ishikawa and HEC-1A cells. The proliferation of EECs was found 
      to be mammalian target of rapamycin (mTOR) dependent. Interestingly, therapeutic 
      metformin concentrations were not able to activate the classical AMP-activated 
      protein kinase (AMPK) signaling. On the contrary, supratherapeutic metformin 
      concentration (10 mmol/L) inhibited mTOR and activated AMPK signaling. Microarray 
      analysis of metformin-treated HEC-1A cells revealed dose-dependent differential 
      effects on biological pathways associated with translation, ribosomal RNA 
      processing, mitochondrial translation, and cell proliferation. Therapeutic 
      concentrations of metformin upregulated mitochondrial number as demonstrated by 
      increased MitoTracker() Red staining and enhanced succinate dehydrogenase 
      expression; however, higher concentration (10 mmol/L) abrogated the same. Our 
      results suggest that therapeutic concentrations of metformin augment 
      mitochondrial strength and induce mTOR-dependent endometrial cell proliferation.
FAU - Imran, M
AU  - Imran M
AD  - Cell Physiology and Pathology Laboratory, ICMR-National Institute for Research in 
      Reproductive and Child Health, Mumbai, Maharashtra, India.
FAU - Sachdeva, Geetanjali
AU  - Sachdeva G
AD  - Cell Physiology and Pathology Laboratory, ICMR-National Institute for Research in 
      Reproductive and Child Health, Mumbai, Maharashtra, India.
FAU - Menon, Shyla
AU  - Menon S
AD  - Stem Cell Biology Laboratory, ICMR-National Institute for Research in 
      Reproductive and Child Health, Mumbai, Maharashtra, India.
FAU - Das, Dhanjit
AU  - Das D
AD  - Stem Cell Biology Laboratory, ICMR-National Institute for Research in 
      Reproductive and Child Health, Mumbai, Maharashtra, India.
FAU - Davuluri, Sravanthi
AU  - Davuluri S
AD  - Shodhaka Life Sciences Pvt. Ltd., Bengaluru, Karnataka, India.
FAU - Acharya, Kshitish
AU  - Acharya K
AD  - Shodhaka Life Sciences Pvt. Ltd., Bengaluru, Karnataka, India.
AD  - Institute of Bioinformatics and Applied Biotechnology (IBAB), Bengaluru, 
      Karnataka, India.
FAU - Chaudhari, Uddhav
AU  - Chaudhari U
AUID- ORCID: 0000-0002-1551-3840
AD  - Cell Physiology and Pathology Laboratory, ICMR-National Institute for Research in 
      Reproductive and Child Health, Mumbai, Maharashtra, India.
LA  - eng
PT  - Journal Article
DEP - 20221102
PL  - Canada
TA  - Can J Physiol Pharmacol
JT  - Canadian journal of physiology and pharmacology
JID - 0372712
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Female
MH  - Humans
MH  - AMP-Activated Protein Kinases/metabolism
MH  - Cell Proliferation
MH  - *Endometrial Neoplasms
MH  - Epithelial Cells/metabolism
MH  - *Metformin/pharmacology/therapeutic use
MH  - TOR Serine-Threonine Kinases/metabolism
OTO - NOTNLM
OT  - endometrium
OT  - metformin
OT  - microarray
OT  - mitochondria
OT  - proliferation
EDAT- 2022/11/03 06:00
MHDA- 2023/01/13 06:00
CRDT- 2022/11/02 17:42
PHST- 2022/11/03 06:00 [pubmed]
PHST- 2023/01/13 06:00 [medline]
PHST- 2022/11/02 17:42 [entrez]
AID - 10.1139/cjpp-2022-0307 [doi]
PST - ppublish
SO  - Can J Physiol Pharmacol. 2023 Jan 1;101(1):52-64. doi: 10.1139/cjpp-2022-0307. 
      Epub 2022 Nov 2.