Interleukin-6 sensitizes TNF-α and TRAIL/Apo2L dependent cell death through upregulation of death receptors in human cancer cells
| Autor: | Akira Kazaana, Yoshinari Ozawa, Yutaka Suzuki, Toshiaki Takei, Sodai Yoshimura, Hisashi Tadakuma, Emiko Sano, Atsuo Yoshino, Yuya Hanashima, Takuya Ueda |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Programmed cell death Apoptosis Flow cytometry TNF-Related Apoptosis-Inducing Ligand 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Cell Line Tumor Neoplasms medicine Humans Interleukin 6 Molecular Biology Caspase Caspase 8 biology medicine.diagnostic_test Cell Death Chemistry Caspase 3 Interleukin-6 Tumor Necrosis Factor-alpha Cell Biology Receptors Death Domain Receptors TNF-Related Apoptosis-Inducing Ligand 030104 developmental biology Proto-Oncogene Proteins c-bcl-2 SKBR3 030220 oncology & carcinogenesis Caspases biology.protein Cancer research Antibody Apoptosis Regulatory Proteins Signal Transduction |
| Zdroj: | Biochimica et biophysica acta. Molecular cell research. 1868(7) |
| ISSN: | 1879-2596 |
| Popis: | Interleukin-6 (IL-6) enhanced TNF-α and TRAIL/Apo2L induced cell death in various human cancer cells derived from malignant glioma, melanoma, breast cancer and leukemia, although the effect was not detected with IL-6 alone. The effects of IL-6 using SKBR3 cells were associated with the generation of apoptotic cells as analyzed by fluorescence microscopy and flow cytometry. IL-6 activated p53 and upregulated TRAIL death receptors (DR-4 and DR-5) and stimulated the TNF-α and TRAIL dependent extrinsic apoptotic pathway without activation of the p53 mediated intrinsic apoptotic pathway. TNF-α and TRAIL induced cleavage of caspase-8 and caspase-3 was more enhanced by IL-6, although these caspases were not cleaved by IL-6 alone. The dead cell generation elicited by the combination with IL-6 was blocked by anti-human TRAIL R2/TNFRSF10B Fc chimera antibody which can neutralize the DR-5 mediated death signal. These findings indicate that IL-6 could contribute to the enhancement of TNF-α or TRAIL induced apoptosis through p53 dependent upregulation of DR-4 and DR-5. The data suggest that a favorable therapeutic interaction could occur between TNF-α or TRAIL and IL-6, and provide an experimental basis for rational clinical treatments in various cancers. |
| Databáze: | OpenAIRE |
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