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

Emiko Sano*, Akira Kazaana, Hisashi Tadakuma, Toshiaki Takei, Sodai Yoshimura, Yuya Hanashima, Yoshinari Ozawa, Atsuo Yoshino, Yutaka Suzuki, Takuya Ueda

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number119037
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1868
Issue number7
DOIs
Publication statusPublished - 2021 Jun

Keywords

  • Activation of fas and TRAIL mediated extrinsic apoptotic pathways by IL-6
  • Enhancement of cleavage of caspase-8 and caspase-3 by IL-6
  • Promotion of TNF-α, TRAIL/Apo2L dependent cell death by IL-6
  • p53 dependent upregulation of death receptors by IL-6

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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