Rapamycin inhibits both motility through down-regulation of p-STAT3 (S727) by disrupting the mTORC2 assembly and peritoneal dissemination in sarcomatoid cholangiocarcinoma
| Autor: | Dae Ghon Kim, Jung Hee Kwon, Nam Gyu Lee, Kwan Yong Choi, Hyung Jin Cha, Sun Mi Hong, Hong Gil Nam, Chang Wook Park, Young Sung Yun |
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| Rok vydání: | 2012 |
| Předmět: |
Male
STAT3 Transcription Factor Cancer Research Blotting Western Down-Regulation Mice Nude Motility Apoptosis Mechanistic Target of Rapamycin Complex 2 Biology Real-Time Polymerase Chain Reaction mTORC2 Cholangiocarcinoma Immunoenzyme Techniques Mice Cell Movement Cell Adhesion Tumor Cells Cultured medicine Animals Humans Immunoprecipitation RNA Messenger Phosphorylation Protein kinase B Peritoneal Neoplasms PI3K/AKT/mTOR pathway Cell Proliferation Sirolimus Reverse Transcriptase Polymerase Chain Reaction TOR Serine-Threonine Kinases RPTOR General Medicine Bile Ducts Intrahepatic Bile Duct Neoplasms Oncology Multiprotein Complexes Cancer research Proto-Oncogene Proteins c-akt medicine.drug |
| Zdroj: | Clinical & Experimental Metastasis. 30:177-187 |
| ISSN: | 1573-7276 0262-0898 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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