TY - JOUR
T1 - Interleukin-6 sensitizes TNF-α and TRAIL/Apo2L dependent cell death through upregulation of death receptors in human cancer cells
AU - Sano, Emiko
AU - Kazaana, Akira
AU - Tadakuma, Hisashi
AU - Takei, Toshiaki
AU - Yoshimura, Sodai
AU - Hanashima, Yuya
AU - Ozawa, Yoshinari
AU - Yoshino, Atsuo
AU - Suzuki, Yutaka
AU - Ueda, Takuya
N1 - Funding Information:
This study was supported in part by a grant from Toray Industries Inc. (Tokyo, Japan). The authors are grateful to Dr. Kin-ichiro Miura and Dr. Kouhei Tsumoto, Graduate School of Frontier Sciences, the University of Tokyo, for their invaluable discussions.
Publisher Copyright:
© 2021 Elsevier B.V.
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
KW - Activation of fas and TRAIL mediated extrinsic apoptotic pathways by IL-6
KW - Enhancement of cleavage of caspase-8 and caspase-3 by IL-6
KW - Promotion of TNF-α, TRAIL/Apo2L dependent cell death by IL-6
KW - p53 dependent upregulation of death receptors by IL-6
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U2 - 10.1016/j.bbamcr.2021.119037
DO - 10.1016/j.bbamcr.2021.119037
M3 - Article
C2 - 33839168
AN - SCOPUS:85104146096
SN - 0167-4889
VL - 1868
JO - Biochimica et Biophysica Acta - Molecular Cell Research
JF - Biochimica et Biophysica Acta - Molecular Cell Research
IS - 7
M1 - 119037
ER -