PHA665752 inhibits the HGF-stimulated migration and invasion of cells by blocking PI3K/AKT pathway in uveal melanoma
Autor: | Qiu Gh, Xiuping Chen, Zhenning Wang, He C, Liu L, Zheng D, Ma N |
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Rok vydání: | 2017 |
Předmět: |
Uveal Neoplasms
0301 basic medicine Cancer Research Indoles Mice Nude Motility Biology Metastasis Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Movement Cell Line Tumor medicine Animals Humans Neoplasm Invasiveness LY294002 Sulfones Melanoma Protein kinase B PI3K/AKT/mTOR pathway Hepatocyte Growth Factor medicine.disease Xenograft Model Antitumor Assays Cell biology 030104 developmental biology Oncology chemistry Cell culture 030220 oncology & carcinogenesis Cancer research Phosphorylation Proto-Oncogene Proteins c-akt Signal Transduction |
Zdroj: | Neoplasma. 64:377-388 |
ISSN: | 1338-4317 |
DOI: | 10.4149/neo_2017_308 |
Popis: | HGF/c-MET is frequently associated with tumor metastasis in many cancers, including uveal melanoma (UM). PHA665752, a selective c-MET inhibitor, exhibits anticancer activity through inhibiting cell motility in some cancers. In this study, we investigated the effects of PHA665752 on UM cell lines M17 and SP6.5. Our data show that HGF stimulated the motility of UM cells, and induced the activation of both c-MET and PI3K/AKT, but not ERK1/2. Moreover, consistent with the amount of c-MET within the nucleus, PHA665752 significantly inhibited HGF-promoted cell motility and suppressed the phosphorylation of c-MET and PI3K/AKT, but not ERK1/2 induced by HGF. Additionally, the effects of PHA665752 on both the inhibition of HGF-induced cell motility and the suppression of active AKT are similar to those of PI3K inhibitor LY294002. In xenograft models, PHA665752 significantly inhibited tumor growth in nude mice and similarly suppressed the phosphorylation of c-MET and PI3K/AKT. Our current findings, combined with previous results, demonstrate that PHA665752 inhibits HGF-induced motility via the inhibition of PI3K/AKT. This study suggests that targeting HGF/c-MET could be a promising therapeutic strategy for UM by preventing cell motility. |
Databáze: | OpenAIRE |
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