title: The role of phospholipase D in modulating the MTOR signaling pathway in polycystic kidney disease.
abstract: 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.
authors.affiliation: Institute of Physiology, University of Zurich, Zürich, Switzerland.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Andres
authors.initials: A
authors.lastname: Käch
authors.forename: Urs
authors.initials: U
authors.lastname: Ziegler
authors.forename: Albert C M
authors.initials: AC
authors.lastname: Ong
authors.forename: Darren P
authors.initials: DP
authors.lastname: Wallace
authors.forename: Alexandre
authors.initials: A
authors.lastname: Arcaro
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Serra
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D010712:Phosphatidic Acids / Q000494:pharmacology; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007690:Polycystic Kidney Diseases / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D010712:Phosphatidic Acids; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases; D010739:Phospholipase D