PMID- 14729629
OWN - NLM
STAT- MEDLINE
DCOM- 20040401
LR  - 20211203
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 64
IP  - 1
DP  - 2004 Jan 1
TI  - Roles of phosphatidylinositol 3'-kinase and mammalian target of rapamycin/p70 
      ribosomal protein S6 kinase in K-Ras-mediated transformation of intestinal 
      epithelial cells.
PG  - 229-35
AB  - Phosphatidylinositol 3'-kinase (PI3K) activity is required for Ras- mediated 
      transformation of intestinal epithelial cells (IECs). The mammalian target of 
      rapamycin (mTOR) and its downstream pathways control the translation of specific 
      mRNAs that are required for cell proliferation and transformation. Here, we 
      elucidated the roles of PI3K and mTOR in K-Ras-mediated transformation of IECs 
      (IEC-6). Induction of K-Ras activated PI3K and mTOR in IECs. p70 ribosomal 
      protein S6 kinase activity was induced by K-Ras in a PI3K- and mTOR-dependent 
      manner. K-Ras did not significantly alter the phosphorylation of eukaryotic 
      initiation factor 4E-binding protein 1. Treatment with either LY-294002 or 
      rapamycin inhibited IEC proliferation and resulted in G(1) growth arrest. 
      However, it was noted that inhibition of mTOR enhanced K-Ras-mediated 
      morphological transformation and increased invasiveness of IECs in a 
      mitogen-activated protein/extracellular signal-regulated kinase-dependent manner. 
      Furthermore, inhibition of PI3K or mTOR impaired the growth of an array of colon 
      cancer cells. Spindle transformation, reduced E-cadherin, and increased 
      invasiveness were observed in LY-294002-treated Moser cells. Thus, our results 
      suggest that K-Ras-mediated transformation of IECs involves activation of the 
      PI3K/mTOR pathway. Inhibition of PI3K/mTOR activity leads to G(1) growth arrest 
      of transformed IECs. On the other hand, inhibition of PI3K or mTOR may induce the 
      epithelial to mesenchymal transdifferentiation of IECs under certain 
      circumstances.
FAU - Shao, Jinyi
AU  - Shao J
AD  - Department of Surgery and Sealy Center for Cancer Cell Biology, University of 
      Texas Medical Branch, Galveston, Texas 77555, USA.
FAU - Evers, B Mark
AU  - Evers BM
FAU - Sheng, Hongmiao
AU  - Sheng H
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (RNA, Messenger)
RN  - 367-93-1 (Isopropyl Thiogalactoside)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Cell Differentiation
MH  - Cell Division
MH  - Cell Line
MH  - *Cell Transformation, Neoplastic/*genetics
MH  - Colonic Neoplasms/genetics
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/pharmacology
MH  - *Genes, ras
MH  - Humans
MH  - Intestinal Mucosa/drug effects/enzymology/*pathology
MH  - Isopropyl Thiogalactoside/pharmacology
MH  - Kinetics
MH  - MAP Kinase Signaling System
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Protein Kinases/*metabolism
MH  - RNA, Messenger/genetics
MH  - Rectal Neoplasms/genetics
MH  - Ribosomal Protein S6 Kinases/*metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/*metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Transcription, Genetic
EDAT- 2004/01/20 05:00
MHDA- 2004/04/02 05:00
CRDT- 2004/01/20 05:00
PHST- 2004/01/20 05:00 [pubmed]
PHST- 2004/04/02 05:00 [medline]
PHST- 2004/01/20 05:00 [entrez]
AID - 10.1158/0008-5472.can-03-1859 [doi]
PST - ppublish
SO  - Cancer Res. 2004 Jan 1;64(1):229-35. doi: 10.1158/0008-5472.can-03-1859.