TNF-α-induced down-regulation of type I interferon receptor contributes to acquired resistance of cervical squamous cancer to Cisplatin

• Published in: Journal of antibiotics 2024-02, Vol.77 (2), p.102-110
• Main Authors: Yu, Yani, Yu, Jia, Cui, Xiaorong, Sun, Xin, Yu, Xiaohui
• Format: Article
• Language: English
• Subjects: 13/1; 13/51; 14/19; 14/3; 38/47; 38/5; 42/100; 42/44; 45/43; 631/61; 639/638; Ammonium; Anthracenes; Apoptosis; Bacteriology; Biomedical and Life Sciences; Bioorganic Chemistry; c-Jun protein; Cancer; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - metabolism; Casein; Caspase; Cell Line, Tumor; Cell proliferation; Cell viability; Cervical cancer; Cisplatin; Cisplatin - metabolism; Cisplatin - pharmacology; Down-Regulation; Enzyme inhibitors; Female; Humans; Interferon; Kinases; Life Sciences; Medicinal Chemistry; Microbiology; Organic Chemistry; Proline - analogs & derivatives; Protease inhibitors; Proteinase inhibitors; Receptor, Interferon alpha-beta - genetics; Receptor, Interferon alpha-beta - metabolism; Receptors; Sensitivity; Signal transduction; Thiocarbamates; Transcription factors; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Uterine Cervical Neoplasms - drug therapy; α-Interferon
• ISSN: 0021-8820; 1881-1469
• DOI: 10.1038/s41429-023-00686-z

We aimed to investigate the effects of tumor necrosis factor (TNF)-α on the expression of interferon α/β receptor subunit 1 (IFNAR1) and cervical squamous cancer (CSCC) resistance to Cisplatin, as well as the underlying mechanisms. Kaplan–Meier analysis was used to plot the overall survival curves. SiHa cells were treated with 20 ng/ml TNF-α to determine cell proliferation in human CSCC cells and the expression of IFNAR1. The effects of TNF-α on the downstream signaling pathway, including casein kinase 1α (CK1α), were investigated using the caspase protease inhibitor FK009, the c-Jun kinase inhibitor SP600125, and the nuclear factor kappa-B inhibitor ammonium pyrrolidinedithiocarbamate (PDTC). TNF-α induced down-regulation of IFNAR1 in human CSCC cells and promoted proliferation of SiHa cells. SiHa cells were transfected with the catalytic inactive mutant CK1α K49A, and the ability of TNF-α to induce down-regulation of IFNAR1 expression was found to be significantly diminished in this context. FK009 and PDTC had no obvious effect on the expression of CK1α, however, SP600125 significantly reduced the expression of CK1α in the presence of TNF-α. SiHa cells treated with TNF-α showed reduced sensitivity to Cisplatin and exhibited higher cell viability, while the sensitivity of SiHa cells to Cisplatin was restored after treatment with CK1α inhibitor D4476. Additionally, we constructed a TNF-α overexpressing SiHa cell line and a transplanted tumor model. The results were similar to those of in vitro efficacy. We demonstrate that TNF-α-induced down-regulation of type I interferon receptor contributes to acquired resistance of cervical squamous cancer to Cisplatin.