Abstract
Cholangiocarcinoma (CC) is a malignant epithelium neoplasm that originates from the bile epithelium and for which there are few therapeutic strategies. The mTOR pathway involved in many cellular processes was reported to be up-regulated in various cancers. We investigated the activation of the AKT/mTOR pathway in CC cell lines with different degrees of dedifferentiation and found that rapamycin could suppress the motility and the peritoneal dissemination of sarcomatoid SCK cells. Inhibition of the mTOR pathway with rapamycin decreased significantly the number of tumor nodules and prolonged the survival rates of nude mice inoculated with sarcomatoid CC cells. Prolonged treatments with rapamycin were found to disrupt the mTORC2 assembly and to reduce the phosphorylation of STAT3 at Ser 727. Rapamycin decreased both mRNA and protein levels of MMP2 and Twist1, which are regulated by STAT3 and associated with cancer metastasis. The overexpression of STAT3 S727A lacking the phosphorylation site resulted in significantly less sensitivity to rapamycin than the overexpression of STAT3 WT. Taken together, our results suggest that rapamycin could suppress the motility of sarcomatoid CC by down-regulating p-STAT3 (S727) through the impairment of mTORC2 assembly.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Bile Duct Neoplasms / drug therapy*
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Bile Duct Neoplasms / metabolism
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Bile Duct Neoplasms / pathology
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Bile Ducts, Intrahepatic / drug effects*
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Bile Ducts, Intrahepatic / metabolism
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Bile Ducts, Intrahepatic / pathology
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Blotting, Western
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Cell Adhesion / drug effects
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Cell Movement / drug effects*
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Cell Proliferation / drug effects
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Cholangiocarcinoma / drug therapy*
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Cholangiocarcinoma / metabolism
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Cholangiocarcinoma / pathology
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Down-Regulation
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Humans
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Immunoenzyme Techniques
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Immunoprecipitation
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Male
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Mechanistic Target of Rapamycin Complex 2
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Mice
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Mice, Nude
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism*
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Peritoneal Neoplasms / drug therapy*
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Peritoneal Neoplasms / metabolism
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Peritoneal Neoplasms / secondary
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Phosphorylation / drug effects
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism*
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Sirolimus / pharmacology*
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism*
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Tumor Cells, Cultured
Substances
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Multiprotein Complexes
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RNA, Messenger
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STAT3 Transcription Factor
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Mechanistic Target of Rapamycin Complex 2
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Sirolimus