| Autor: |
Kazuhiko Nakagawa, Kazuto Nishio, Masahiro Fukuoka, Kazuyoshi Yanagihara, Tokuzo Arao, Kiyoko Kuwata, Yuki Yamada, Erina Hatashita, Ken Takezawa, Kunio Okamoto, Takeshi Yoshida, Isamu Okamoto, Wataru Okamoto |
| Rok vydání: |
2023 |
| DOI: |
10.1158/1535-7163.c.6532190 |
| Popis: |
Therapeutic strategies that target c-Src hold promise for a wide variety of cancers. We have now investigated both the effects of dasatinib, which inhibits the activity of c-Src and several other kinases, on cell growth as well as the mechanism of dasatinib resistance in human gastric cancer cell lines. Immunoblot analysis revealed the activation of c-Src at various levels in most gastric cancer cell lines examined. Dasatinib inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) and induced G1 arrest, as revealed by flow cytometry, in a subset of responsive cell lines. In other responsive cell lines, dasatinib inhibited both ERK and AKT phosphorylation and induced apoptosis, as revealed by an increase in caspase-3 activity and cleavage of poly(ADP-ribose) polymerase. Depletion of c-Src by RNA interference also induced G1 arrest or apoptosis in dasatinib-responsive cell lines, indicating that the antiproliferative effect of dasatinib is attributable to c-Src inhibition. Gastric cancer cell lines positive for the activation of MET were resistant to dasatinib. Dasatinib had no effect on ERK or AKT signaling, whereas the MET inhibitor PHA-665752 induced apoptosis in these cells. The subsets of gastric cancer cells defined by a response to c-Src or MET inhibitors were distinct and nonoverlapping. Our results suggest that c-Src is a promising target for the treatment of gastric cancer and that analysis of MET amplification might optimize patient selection for treatment with c-Src inhibitors. Mol Cancer Ther; 9(5); 1188–97. ©2010 AACR. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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