Transmembrane TNF-alpha promotes chemoresistance in breast cancer cells.

Autor: Zhang Z; Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Lin G; Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Yan Y; Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Li X; Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Hu Y; Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Wang J; Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Yin B; Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Wu Y; Department of Thyroid and Breast Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Li Z; Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. zhuoyali@mails.tjmu.edu.cn., Yang XP; Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. yangxp@hust.edu.cn.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2018 Jun; Vol. 37 (25), pp. 3456-3470. Date of Electronic Publication: 2018 Mar 21.
DOI: 10.1038/s41388-018-0221-4
Abstrakt: Chemoresistance remains a major obstacle to successful treatment of breast cancer. Although soluble tumor necrosis factor-α (sTNF-α) has been implicated in mediating drug-resistance in human cancers, whether transmembrane tumor necrosis factor-α (tmTNF-α) plays a role in chemoresistance remains unclear. Here we found that over 50% of studied patients expressed tmTNF-α at high levels in breast cancer tissues and tmTNF-α expression positively correlated with resistance to anthracycline chemotherapy. Alteration of tmTNF-α expression changed the sensitivity of primary human breast cancer cells and breast cancer cell lines to doxorubicin (DOX). Overexpression of N-terminal fragment (NTF) of tmTNF-α, a mutant form with intact intracellular domain of tmTNF-α to transmit reverse signals, induced DOX-resistance. Mechanistically, the tmTNF-α/NTF-ERK-GST-π axis and tmTNF-α/NTF-NF-κB-mediated anti-apoptotic functions were required for tmTNF-α-induced DOX-resistance. In a xenograft mouse model, the combination of tmTNF-α suppression with chemotherapy significantly enhanced the efficacy of DOX. Our data indicate that tmTNF-α mediates DOX-resistance through reverse signaling and targeting tmTNF-α may be beneficial for the treatment of DOX-resistant breast cancer.
Databáze: MEDLINE
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