EGFR tyrosine kinase inhibitors promote pro-caspase-8 dimerization that sensitizes cancer cells to DNA-damaging therapy
| Autor: | Yan Yu, Zhen Hua Li, Rong Deng, Lin Jiao, Yun Tian Li, Peng Fei Kong, Wen Dan Chen, Xiao Feng Zhu, Xuan Li, Jiao Ji, Gong Kan Feng, Rui Yan Wu, Xiao Jun Qian |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
MAPK/ERK pathway
medicine.drug_class Blotting Western Apoptosis Breast Neoplasms Pharmacology Lapatinib Transfection doxorubicin Tyrosine-kinase inhibitor caspase-8 Erlotinib Hydrochloride breast cancer Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols Medicine Humans Immunoprecipitation Epidermal growth factor receptor Protein Kinase Inhibitors EGFR inhibitors Caspase 8 biology sequential application business.industry ErbB Receptors Oncology Cancer cell biology.protein Quinazolines Erlotinib Protein Multimerization business medicine.drug DNA Damage Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | The combination of time and order-dependent chemotherapeutic strategies has demonstrated enhanced efficacy in killing cancer cells while minimizing adverse effects. However, the precise mechanism remains elusive. Our results showed that pre-treatment of MCF-7 and MDA-MB-468 cells with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib or lapatinib significantly enhanced the cytotoxic effects of DNA-damaging agents compared to coadministration of the EGFR inhibitor and DNA-damaging agent. Sequential application of erlotinib and doxorubicin increased activated caspase-8 by promoting pro-caspase-8 homodimerization and autocatalytical cleavage, whereas coadministration did not. We found that EGFR inhibitors promoted pro-caspase-8 homodimerization by inhibiting ERK pathway signaling, while doxorubicin promoted it. Our data highlight that ERK has the potential to inhibit the formation of pro-caspase-8 homodimers by phosphorylating pro-caspase-8 at S387. In conclusion, the pretreatment of EGFR tyrosine kinase inhibitors promote pro-caspase-8 dimerization that sensitizes cancer cells to DNA-damaging agents. Our findings provide rationale for novel strategies for the implementation of combined targeted and cytotoxic chemotherapy within a new framework of time and order-dependent therapy. |
| Databáze: | OpenAIRE |
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