Growth of chronic myeloid leukemia cells is inhibited by infection with Ad-SH2-HA adenovirus that disrupts Grb2-Bcr-Abl complexes
| Autor: | Wei-Xi Cao, Zhi Peng, Jing Shi, Shi-Feng Huang, Wenli Feng, Ying Yuan, Hong-Wei Luo, Chun-li Li, Zong-Gan Huang |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
Genetic Vectors Fusion Proteins bcr-abl Apoptosis HL-60 Cells Biology Adenoviridae Proto-Oncogene Proteins p21(ras) src Homology Domains hemic and lymphatic diseases Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive Gene Order medicine Humans Kinase activity neoplasms Protein kinase B Cell Proliferation GRB2 Adaptor Protein Mitogen-Activated Protein Kinase Kinases Binding Sites HEK 293 cells Myeloid leukemia General Medicine medicine.disease Enzyme Activation Leukemia Protein Transport HEK293 Cells Oncology Cell culture biology.protein Cancer research GRB2 K562 Cells Proto-Oncogene Proteins c-akt K562 cells Protein Binding |
| Zdroj: | Oncology reports. 25(5) |
| ISSN: | 1791-2431 |
| Popis: | The persistence of Bcr-Abl-positive cells in patients on imatinib therapy indicates that inhibition of the Bcr-Abl kinase activity alone might not be sufficient to eradicate the leukemia cells. Many downstream effectors of Bcr-Abl have been described, including activation of both the Grb2-SoS-Ras-MAPK and Grb2-Gab2-PI3K-Akt pathways. The Bcr-Abl-Grb2 interaction, which is mediated by the direct interaction of the Grb2 SH2 domain with the phospho-Bcr-Abl Y177, is required for activation of these signaling pathways. Therefore, disrupting their interaction represents a potential therapeutic strategy for inhibiting the oncogenic downstream signals of Bcr-Abl. Adenovirus Ad-SH2-HA expressing the Grb2 SH2 domain was constructed and applied in this study. As expected, Ad-SH2-HA efficiently infected CML cells and functioned by binding to the phospho-Bcr-Abl Y177 site, competitively disrupting the Grb2 SH2-phospho-Bcr-Abl Y177 complex. They induced potent anti-proliferation and apoptosis-inducing effects in CML cell lines. Moreover, the Ras, MAPK and Akt activities were significantly reduced in the Ad-SH2-HA treated cells. These were not observed with the point-mutated control adenovirus Ad-Sm-HA with abolished phospho-Bcr-Abl Y177 binding sites. These data indicate that, in addition to the direct targeting of Bcr-Abl, selective inhibition of its downstream signaling pathways may be a therapeutic option for CML, and the Ad-SH2-HA-mediated killing strategy could be explored as a promising anti-leukemia agent in CML. |
| Databáze: | OpenAIRE |
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