Interleukin-6 sensitizes TNF-α and TRAIL/Apo2L dependent cell death through upregulation of death receptors in human cancer cells

• Published in: Biochimica et biophysica acta. Molecular cell research 2021-06, Vol.1868 (7), p.119037-119037, Article 119037
• Main Authors: Sano, Emiko, Kazaana, Akira, Tadakuma, Hisashi, Takei, Toshiaki, Yoshimura, Sodai, Hanashima, Yuya, Ozawa, Yoshinari, Yoshino, Atsuo, Suzuki, Yutaka, Ueda, Takuya
• Format: Article
• Language: English
• Subjects: Activation of fas and TRAIL mediated extrinsic apoptotic pathways by IL-6; Enhancement of cleavage of caspase-8 and caspase-3 by IL-6; p53 dependent upregulation of death receptors by IL-6; Promotion of TNF-α, TRAIL/Apo2L dependent cell death by IL-6
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2021.119037

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. •IL-6 enhanced TNF-α and TRAIL/Apo2L induced cell death in human cancer cells.•IL-6 promotes cell death through p53 dependent upregulation of death receptors.•IL-6 sensitizes fas and TRAIL mediated extrinsic apoptotic pathway.•IL-6 enhanced the cleavage of caspase-8 and caspase-9 promoted by TNF-α and TRAIL.