PMID- 24009738
OWN - NLM
STAT- MEDLINE
DCOM- 20140416
LR  - 20211203
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 8
DP  - 2013
TI  - The role of phospholipase D in modulating the MTOR signaling pathway in 
      polycystic kidney disease.
PG  - e73173
LID - 10.1371/journal.pone.0073173 [doi]
LID - e73173
AB  - The mammalian target of rapamycin (mTOR) signaling pathway is aberrantly 
      activated in polycystic kidney disease (PKD). Emerging evidence suggests that 
      phospholipase D (PLD) and its product phosphatidic acid (PA) regulate mTOR 
      activity. In this study, we assessed in vitro the regulatory function of PLD and 
      PA on the mTOR signaling pathway in PKD. We found that the basal level of PLD 
      activity was elevated in PKD cells. Targeting PLD by small molecule inhibitors 
      reduced cell proliferation and blocked mTOR signaling, whereas exogenous PA 
      stimulated mTOR signaling and abolished the inhibitory effect of PLD on PKD cell 
      proliferation. We also show that blocking PLD activity enhanced the sensitivity 
      of PKD cells to rapamycin and that combining PLD inhibitors and rapamycin 
      synergistically inhibited PKD cell proliferation. Furthermore, we demonstrate 
      that targeting mTOR did not induce autophagy, whereas targeting PLD induced 
      autophagosome formation. Taken together, our findings suggest that deregulated 
      mTOR pathway activation is mediated partly by increased PLD signaling in PKD 
      cells. Targeting PLD isoforms with pharmacological inhibitors may represent a new 
      therapeutic strategy in PKD.
FAU - Liu, Yang
AU  - Liu Y
AD  - Institute of Physiology, University of Zurich, Zurich, Switzerland.
FAU - Kach, Andres
AU  - Kach A
FAU - Ziegler, Urs
AU  - Ziegler U
FAU - Ong, Albert C M
AU  - Ong AC
FAU - Wallace, Darren P
AU  - Wallace DP
FAU - Arcaro, Alexandre
AU  - Arcaro A
FAU - Serra, Andreas L
AU  - Serra AL
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130823
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Phosphatidic Acids)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.4.4 (Phospholipase D)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Cell Proliferation/drug effects
MH  - Disease Models, Animal
MH  - Drug Synergism
MH  - Enzyme Activation/drug effects
MH  - Enzyme Inhibitors/pharmacology
MH  - Epithelial Cells/drug effects/metabolism
MH  - Humans
MH  - Kidney Tubules/drug effects/metabolism
MH  - Male
MH  - Models, Biological
MH  - Phagosomes/drug effects/metabolism
MH  - Phosphatidic Acids/pharmacology
MH  - Phospholipase D/antagonists & inhibitors/*metabolism
MH  - Polycystic Kidney Diseases/*metabolism
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Rats
MH  - *Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC3751888
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/09/07 06:00
MHDA- 2014/04/17 06:00
PMCR- 2013/08/23
CRDT- 2013/09/07 06:00
PHST- 2013/03/27 00:00 [received]
PHST- 2013/07/17 00:00 [accepted]
PHST- 2013/09/07 06:00 [entrez]
PHST- 2013/09/07 06:00 [pubmed]
PHST- 2014/04/17 06:00 [medline]
PHST- 2013/08/23 00:00 [pmc-release]
AID - PONE-D-13-13150 [pii]
AID - 10.1371/journal.pone.0073173 [doi]
PST - epublish
SO  - PLoS One. 2013 Aug 23;8(8):e73173. doi: 10.1371/journal.pone.0073173. eCollection 
      2013.