Targeting EphA4 abrogates intrinsic resistance to chemotherapy in well-differentiated cervical cancer cell line
| Autor: | Feixin Liang, Toshiyuki Nakasone, Akira Arasaki, Takao Kinjo, Shinichiro Kina, Hideyuki Yamamoto |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Adult
0301 basic medicine Down-Regulation Uterine Cervical Neoplasms Receptor tyrosine kinase HeLa 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine LYN Cell Line Tumor medicine Humans Molecular Targeted Therapy Protein Kinase Inhibitors Aged Aged 80 and over Pharmacology Cisplatin biology Kinase Interleukins Receptor EphA4 Cell Differentiation Tyrosine phosphorylation Combination chemotherapy Middle Aged biology.organism_classification Minimal residual disease src-Family Kinases 030104 developmental biology chemistry Drug Resistance Neoplasm 030220 oncology & carcinogenesis biology.protein Cancer research Female medicine.drug |
| Zdroj: | European Journal of Pharmacology. 840:70-78 |
| ISSN: | 0014-2999 |
| Popis: | Alkylating reagent chemotherapy for human cancers is not curative, and relapse occurs due to the continued presence of tumor cells, referred to as minimal residual disease (MRD). The survival of MRD cells after chemotherapy, a phenomenon referred to as intrinsic resistance, depends on reactive oxygen species. Well-differentiated regions of the tumor are intrinsically resistant to chemotherapy. Receptor tyrosine kinase erythropoietin-producing human hepatocellular receptor A4 (EphA4) protein is highly expressed in the well-differentiated tumor-derived cervical cancer cell line Caski, but not in poorly differentiated tumor-derived cervical cancer cell lines such as HeLa or SiHa. Here, we report that reactive oxygen species produced by cisplatin exposure induce tyrosine phosphorylation of EphA4. After observing that EphA4 is activated by cisplatin, we rationalized a combination chemotherapy that induces well-differentiated cervical cancer death. Pharmacological inhibition of EphA4 increased cisplatin-induced cell death in Caski cells. Moreover, we observed increased expression levels of the senescence marker cyclin-dependent kinase inhibitor 2A (p16) in the absence of EphA4 kinase function after stimulation of Caski cells with cisplatin exposure. Mechanistically, cisplatin induces chemotherapy resistance of Caski cells by upregulating Lyn, a Src family kinase (SFK) that interacts with EphA4, through a pathway involving reactive oxygen species. Thus, the reactive oxygen species-SFK-EphA4 axis presents new potential drug targets for chemotherapy resistance. |
| Databáze: | OpenAIRE |
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