Novel β-phenylacrylic acid derivatives exert anti-cancer activity by inducing Src-mediated apoptosis in wild-type KRAS colon cancer
| Autor: | Yunna Lee, Jee H. Jung, Su Jin Kim, Sujin Son, Eunok Im, Do Hyun Kim, Min Jae Kim, Yunjin Jung, Gwangbeom Heo, Jieun Choo, Wooseong Kim, Tae Hwan Noh, Hae Young Chung, Hyung Ryong Moon |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Immunology Antineoplastic Agents Apoptosis medicine.disease_cause Article Proto-Oncogene Proteins p21(ras) 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Gefitinib Cell Line Tumor medicine Humans Epidermal growth factor receptor lcsh:QH573-671 Phosphorylation Protein Kinase Inhibitors EGFR inhibitors biology lcsh:Cytology Chemistry Kinase JNK Mitogen-Activated Protein Kinases Cell Biology Protein-Tyrosine Kinases HCT116 Cells ErbB Receptors Genes src src-Family Kinases 030104 developmental biology 030220 oncology & carcinogenesis Colonic Neoplasms Quinazolines Cancer research biology.protein Unfolded protein response KRAS Caco-2 Cells Mitogen-Activated Protein Kinases HT29 Cells Tyrosine kinase Signal Transduction Proto-oncogene tyrosine-protein kinase Src medicine.drug |
| Zdroj: | Cell Death & Disease Cell Death and Disease, Vol 9, Iss 9, Pp 1-17 (2018) |
| ISSN: | 2041-4889 |
| Popis: | Many stress conditions including chemotherapy treatment is known to activate Src and under certain condition Src can induce the apoptotic signal via c-Jun N-terminal kinase (JNK) activation. Here we report that the newly synthesized β-phenylacrylic acid derivatives, MHY791 and MHY1036 (MHYs), bind to epidermal growth factor receptor (EGFR) tyrosine kinase domains and function as EGFR inhibitors, having anti-cancer activities selectively in wild-type KRAS colon cancer. Mechanistically, MHYs-induced Src/JNK activation which enhanced their pro-apoptotic effects and therefore inhibition of Src by the chemical inhibitor PP2 or Src siRNA abolished the response. In addition, MHYs generated reactive oxygen species and increased ER stress, and pretreatment with antioxidant-inhibited MHY-induced ER stress, Src activation, and apoptosis. Furthermore, the irreversible EGFR inhibitor PD168393 also activated Src while the reversible EGFR inhibitor gefitinib showed the opposite effect, indicating that MHYs are the irreversible EGFR inhibitor. Collectively, Src can play a key role in apoptosis induced by the novel EGFR inhibitor MHYs, suggesting that activation of Src might prove effective in treating EGFR/wild-type KRAS colon cancer. |
| Databáze: | OpenAIRE |
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