RGD Reference Report - Activation of the PI3K/mTOR pathway is involved in cystic proliferation of cholangiocytes of the PCK rat. - Rat Genome Database

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Activation of the PI3K/mTOR pathway is involved in cystic proliferation of cholangiocytes of the PCK rat.

Authors: Ren, XS  Sato, Y  Harada, K  Sasaki, M  Furubo, S  Song, JY  Nakanuma, Y 
Citation: Ren XS, etal., PLoS One. 2014 Jan 30;9(1):e87660. doi: 10.1371/journal.pone.0087660. eCollection 2014.
RGD ID: 10040950
Pubmed: PMID:24498161   (View Abstract at PubMed)
PMCID: PMC3907540   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0087660   (Journal Full-text)

The polycystic kidney (PCK) rat is an animal model of Caroli's disease as well as autosomal recessive polycystic kidney disease (ARPKD). The signaling pathways involving the mammalian target of rapamycin (mTOR) are aberrantly activated in ARPKD. This study investigated the effects of inhibitors for the cell signaling pathways including mTOR on cholangiocyte proliferation of the PCK rat. Cultured PCK cholangiocytes were treated with rapamycin and everolimus [inhibitors of mTOR complex 1 (mTOC1)], LY294002 [an inhibitor of phosphatidylinositol 3-kinase (PI3K)] and NVP-BEZ235 (an inhibitor of PI3K and mTORC1/2), and the cell proliferative activity was determined in relation to autophagy and apoptosis. The expression of phosphorylated (p)-mTOR, p-Akt, and PI3K was increased in PCK cholangiocytes compared to normal cholangiocytes. All inhibitors significantly inhibited the cell proliferative activity of PCK cholangiocytes, where NVP-BEZ235 had the most prominent effect. NVP-BEZ235, but not rapamycin and everolimus, further inhibited biliary cyst formation in the three-dimensional cell culture system. Rapamycin and everolimus induced apoptosis in PCK cholangiocytes, whereas NVP-BEZ235 inhibited cholangiocyte apoptosis. Notably, the autophagic response was significantly induced following the treatment with NVP-BEZ235, but not rapamycin and everolimus. Inhibition of autophagy using siRNA against protein-light chain3 and 3-methyladenine significantly increased the cell proliferative activity of PCK cholangiocytes treated with NVP-BEZ235. In vivo, treatment of the PCK rat with NVP-BEZ235 attenuated cystic dilatation of the intrahepatic bile ducts, whereas renal cyst development was unaffected. These results suggest that the aberrant activation of the PI3K/mTOR pathway is involved in cystic proliferation of cholangiocytes of the PCK rat, and inhibition of the pathway can reduce cholangiocyte proliferation via the mechanism involving apoptosis and/or autophagy.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
autosomal recessive polycystic kidney disease  ISOAkt1 (Rattus norvegicus)10040950; 10040950protein:increased serine phosphorylation:cholangiocyteRGD 
autosomal recessive polycystic kidney disease  IDA 10040950; 10040950protein:increased serine phosphorylation:cholangiocyteRGD 
autosomal recessive polycystic kidney disease  ISOMtor (Rattus norvegicus)10040950; 10040950protein:increased serine phosphorylation:cholangiocyteRGD 
autosomal recessive polycystic kidney disease  ISOPik3ca (Rattus norvegicus)10040950; 10040950protein:increased expression:cholangiocyteRGD 
autosomal recessive polycystic kidney disease  IEP 10040950protein:increased expression:cholangiocyteRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
negative regulation of cholangiocyte apoptotic process  IMP 10040950 RGD 
positive regulation of cholangiocyte proliferation  IMP 10040950 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Akt1  (AKT serine/threonine kinase 1)
Mtor  (mechanistic target of rapamycin kinase)
Pik3ca  (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha)

Genes (Mus musculus)
Akt1  (thymoma viral proto-oncogene 1)
Mtor  (mechanistic target of rapamycin kinase)
Pik3ca  (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)

Genes (Homo sapiens)
AKT1  (AKT serine/threonine kinase 1)
MTOR  (mechanistic target of rapamycin kinase)
PIK3CA  (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)


Additional Information