Induction of IL-6Rα by ATF3 enhances IL-6 mediated sorafenib and regorafenib resistance in hepatocellular carcinoma

• Published in: Cancer letters Vol. 524; pp. 161 - 171
• Main Authors: Dai, Zichan, Wang, Xiaohan, Peng, Rangxin, Zhang, Binghui, Han, Qi, Lin, Jie, Wang, Jichuang, Lin, Junjin, Jiang, Mingting, Liu, Hekun, Lee, Tae Ho, Lu, Kun Ping, Zheng, Min
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.01.2022; Elsevier Limited
• Subjects: Activating transcription factor 3; Activating Transcription Factor 3 - genetics; Animals; Antibodies; Apoptosis - drug effects; ATF3; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell Proliferation; Cytokines; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Gene Expression Regulation, Neoplastic - drug effects; HCC; Hepatocellular carcinoma; Humans; Hybridization; IL-6Rα; Inhibitor drugs; Interleukin 6; Interleukin-6 - genetics; Laboratory animals; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Medical prognosis; Mice; Patients; Phenylurea Compounds - pharmacology; Phosphorylation; Pyridines - pharmacology; Receptors, Interleukin-6 - genetics; Regorafenib; Signal transduction; Sorafenib; Sorafenib - pharmacology; Stat3 protein; Targeted cancer therapy; Transcription activation; Transcription factors; Tumors; Tyrosine; Xenograft Model Antitumor Assays; Xenografts; China; Regorafenib; HCC; IL-6Rα; Sorafenib; ATF3
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2021.10.024

Sorafenib and its derivative regorafenib are the first- and second-line targeted drugs for advanced HCC, respectively. Although both drugs improve overall survival, drug resistance remains the major barrier to their full efficacy. Thus, strategies to enhance sorafenib and regorafenib efficacy against HCC are solely needed. Interleukin-6 receptor alpha (IL-6Rα) is the receptor of IL-6, a multi-functional cytokine, which plays key roles in liver-regeneration, inflammation and development of hepatocellular carcinoma (HCC). Here we show the expression of IL-6Rα was induced in response to sorafenib. Depletion of IL-6Rα abolished IL-6 induced STAT3 phosphorylation at 705th tyrosine and tumor growth of HCC cells under sorafenib treatment. Mechanistically, activating transcription factor 3 (ATF3) was induced in response to sorafenib and subsequently bound to the promoter of IL-6Rα, leading to its transcriptional activation. Depletion of ATF3 or its upstream transcription factor, ATF4, attenuated IL-6Rα induction and IL-6 mediated sorafenib resistance. The ATF4-ATF3-IL-6Rα cascade is also activated by regorafenib. Furthermore, blockade of IL-6Rα with the FDA approved IL-6Rα antibody drug, Sarilumab, drastically attenuated both sorafenib and regorafenib resistance in patient-derived xenograft (PDX) tumors, where human IL-6 could be detected by a novel in situ hybridization technique, named RNAscope. Together, our data reveal that ATF3-mediated IL-6Rα up-regulation promotes both sorafenib and regorafenib resistance in HCC, and targeting IL-6Rα represents a novel therapeutic strategy to enhance sorafenib/regorafenib efficacy for advanced HCC treatment. •Interleukin-6 receptor alpha (IL-6Rα) is induced in response to sorafenib treatment.•IL-6Rα is essential for IL-6 mediated sorafenib resistance in HCC.•Activating transcription factor 3 (ATF3) binds to the IL-6Rα promoter and is involved in IL-6Rα induction.•The ATF3-IL-6Rα cascade is also activated in HCC cells following regorafenib treatment.•Blockade of IL-6Rα sensitizes HCC to sorafenib and regorafenib both ex vivo and invivo.