PMID- 26094588
OWN - NLM
STAT- MEDLINE
DCOM- 20160119
LR  - 20150929
IS  - 1097-4652 (Electronic)
IS  - 0021-9541 (Linking)
VI  - 231
IP  - 1
DP  - 2016 Jan
TI  - Dexamethasone Downregulates SLC7A5 Expression and Promotes Cell Cycle Arrest, 
      Autophagy and Apoptosis in BeWo Cells.
PG  - 233-42
LID - 10.1002/jcp.25076 [doi]
AB  - Synthetic glucocorticoids (GCs) such as dexamethasone (Dex) are widely given to 
      pregnant women to induce maturation and improve viability of preterm infants. 
      Despite the beneficial effects, synthetic GCs have adverse effects on placental 
      growth and nutrient transport system. However, the molecular mechanisms involved 
      in these events remain unknown. Here we use a human placental choriocarcinoma 
      cell line (BeWo) as model to explore the pathway linking amino acids transport 
      with cell viability under Dex challenge. BeWo cells treated with Dex (100 nM) for 
      24 h demonstrated G1/S cell cycle arrest together with enhanced autophagy and 
      apoptosis. Concurrently, the amino acid carrier SLC7A5 was down-regulated in 
      association with impaired cellular amino acids uptake and inhibition of mammalian 
      target of rapamycin (mTOR) signaling. Similar cellular responses were observed in 
      BeWo cells treated with BCH, a classical System L inhibitor which inactivates 
      SLC7A5. The glucocorticoid receptor (GR) antagonist RU486 was able to diminish 
      Dex-induced translocation of GR into nucleus and to abolish these effects. 
      Furthermore, Dex treatment significantly promoted the binding of GR to the 
      proximal promoter sequence of SLC7A5 gene. Taken together, our results show that 
      Dex downregulates SLC7A5 expression via GR-mediated transrepression. The impaired 
      amino acids uptake leads to inhibition of mTOR signaling which in turn causes 
      inhibited proliferation and enhanced autophagy and apoptosis in BeWo cells. These 
      findings indicate that SLC7A5 mediates the effect of Dex on cell viability, thus 
      providing a novel molecular target for the prevention and treatment of 
      Dex-induced cell cycle arrest and apoptosis in placental cells.
CI  - (c) 2015 Wiley Periodicals, Inc.
FAU - He, Bin
AU  - He B
AD  - Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture, 
      Nanjing Agricultural University, Nanjing, China.
FAU - Zhang, Nana
AU  - Zhang N
AD  - Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture, 
      Nanjing Agricultural University, Nanjing, China.
FAU - Zhao, Ruqian
AU  - Zhao R
AD  - Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture, 
      Nanjing Agricultural University, Nanjing, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Cell Physiol
JT  - Journal of cellular physiology
JID - 0050222
RN  - 0 (Glucocorticoids)
RN  - 0 (Large Neutral Amino Acid-Transporter 1)
RN  - 0 (Receptors, Glucocorticoid)
RN  - 7S5I7G3JQL (Dexamethasone)
SB  - IM
MH  - Apoptosis/*drug effects
MH  - Autophagy/*drug effects
MH  - Cell Cycle/drug effects
MH  - Cell Cycle Checkpoints/*drug effects
MH  - Cell Line, Tumor
MH  - Dexamethasone/*pharmacology
MH  - Down-Regulation/drug effects
MH  - Glucocorticoids/*pharmacology
MH  - Humans
MH  - Large Neutral Amino Acid-Transporter 1/*metabolism
MH  - Receptors, Glucocorticoid/metabolism
EDAT- 2015/06/23 06:00
MHDA- 2016/01/20 06:00
CRDT- 2015/06/23 06:00
PHST- 2014/12/17 00:00 [received]
PHST- 2015/06/08 00:00 [accepted]
PHST- 2015/06/23 06:00 [entrez]
PHST- 2015/06/23 06:00 [pubmed]
PHST- 2016/01/20 06:00 [medline]
AID - 10.1002/jcp.25076 [doi]
PST - ppublish
SO  - J Cell Physiol. 2016 Jan;231(1):233-42. doi: 10.1002/jcp.25076.