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Saracatinib impairs the peritoneal dissemination of diffuse-type gastric carcinoma cells resistant to Met and fibroblast growth factor receptor inhibitors.

Yamaguchi H, Takanashi M, Yoshida N, Ito Y, Kamata R, Fukami K, Yanagihara K, Sakai R - Cancer Sci. (2014)

Bottom Line: Saracatinib also effectively impaired peritoneal dissemination of Met-independent and FGFR2-independent SGC cells.Moreover, DGC cell lines exhibited nearly mutually exclusive susceptibility to Met, FGFR and Src inhibitors.These results suggest that DGC have distinct sensitivities to molecular target drugs and that targeting Src is beneficial in the treatment of DGC insensitive to Met and FGFR inhibition.

View Article: PubMed Central - PubMed

Affiliation: Division of Metastasis and Invasion Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.

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Diffuse-type gastric carcinoma (DGC) cell lines with robust overexpression of Met are sensitive to Met inhibitors. (a) DGC and other gastric carcinoma cell lines were subjected to immunoblot analysis with anti-phosphotyrosine (4G10) and anti-Met antibodies. (b) The relative levels of phospho-Met and total Met were quantified from immunoblot data as described in the Materials and Methods. Bars, SD (n = 4 for phospho-Met and 3 for total Met). *P < 0.01, by Student's t-test. (c) DGC cell lines were treated with 300 nM of Met inhibitors for 4 days, and cell viability was assessed. Bars, SD (n = 4). *P < 0.0001 versus other cell lines, by anova with Tukey's test.
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fig01: Diffuse-type gastric carcinoma (DGC) cell lines with robust overexpression of Met are sensitive to Met inhibitors. (a) DGC and other gastric carcinoma cell lines were subjected to immunoblot analysis with anti-phosphotyrosine (4G10) and anti-Met antibodies. (b) The relative levels of phospho-Met and total Met were quantified from immunoblot data as described in the Materials and Methods. Bars, SD (n = 4 for phospho-Met and 3 for total Met). *P < 0.01, by Student's t-test. (c) DGC cell lines were treated with 300 nM of Met inhibitors for 4 days, and cell viability was assessed. Bars, SD (n = 4). *P < 0.0001 versus other cell lines, by anova with Tukey's test.

Mentions: We first examined protein tyrosine phosphorylation in a panel of gastric cancer cell lines (Table S1) by immunoblotting with an anti-phosphotyrosine antibody 4G10 (Fig.1a). The amount of phosphotyrosine-containing proteins mainly distributed from 37 to 250 kDa was greatly elevated in several DGC cell lines, including MKN45, KATO-III, 58As1, 58As9 and SNU-5. Other cell lines exhibited moderate or only a modest level of tyrosine-phosphorylated proteins. Notably, the band pattern of phosphotyrosine-containing proteins in DGC cell lines, which apparently varied among lines, was significantly distinct from those in differentiated gastric cancer cells. These observations indicate that DGC display specific activation of some intracellular signaling pathways involving tyrosine phosphorylation.


Saracatinib impairs the peritoneal dissemination of diffuse-type gastric carcinoma cells resistant to Met and fibroblast growth factor receptor inhibitors.

Yamaguchi H, Takanashi M, Yoshida N, Ito Y, Kamata R, Fukami K, Yanagihara K, Sakai R - Cancer Sci. (2014)

Diffuse-type gastric carcinoma (DGC) cell lines with robust overexpression of Met are sensitive to Met inhibitors. (a) DGC and other gastric carcinoma cell lines were subjected to immunoblot analysis with anti-phosphotyrosine (4G10) and anti-Met antibodies. (b) The relative levels of phospho-Met and total Met were quantified from immunoblot data as described in the Materials and Methods. Bars, SD (n = 4 for phospho-Met and 3 for total Met). *P < 0.01, by Student's t-test. (c) DGC cell lines were treated with 300 nM of Met inhibitors for 4 days, and cell viability was assessed. Bars, SD (n = 4). *P < 0.0001 versus other cell lines, by anova with Tukey's test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317844&req=5

fig01: Diffuse-type gastric carcinoma (DGC) cell lines with robust overexpression of Met are sensitive to Met inhibitors. (a) DGC and other gastric carcinoma cell lines were subjected to immunoblot analysis with anti-phosphotyrosine (4G10) and anti-Met antibodies. (b) The relative levels of phospho-Met and total Met were quantified from immunoblot data as described in the Materials and Methods. Bars, SD (n = 4 for phospho-Met and 3 for total Met). *P < 0.01, by Student's t-test. (c) DGC cell lines were treated with 300 nM of Met inhibitors for 4 days, and cell viability was assessed. Bars, SD (n = 4). *P < 0.0001 versus other cell lines, by anova with Tukey's test.
Mentions: We first examined protein tyrosine phosphorylation in a panel of gastric cancer cell lines (Table S1) by immunoblotting with an anti-phosphotyrosine antibody 4G10 (Fig.1a). The amount of phosphotyrosine-containing proteins mainly distributed from 37 to 250 kDa was greatly elevated in several DGC cell lines, including MKN45, KATO-III, 58As1, 58As9 and SNU-5. Other cell lines exhibited moderate or only a modest level of tyrosine-phosphorylated proteins. Notably, the band pattern of phosphotyrosine-containing proteins in DGC cell lines, which apparently varied among lines, was significantly distinct from those in differentiated gastric cancer cells. These observations indicate that DGC display specific activation of some intracellular signaling pathways involving tyrosine phosphorylation.

Bottom Line: Saracatinib also effectively impaired peritoneal dissemination of Met-independent and FGFR2-independent SGC cells.Moreover, DGC cell lines exhibited nearly mutually exclusive susceptibility to Met, FGFR and Src inhibitors.These results suggest that DGC have distinct sensitivities to molecular target drugs and that targeting Src is beneficial in the treatment of DGC insensitive to Met and FGFR inhibition.

View Article: PubMed Central - PubMed

Affiliation: Division of Metastasis and Invasion Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.

Show MeSH
Related in: MedlinePlus