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Title: Interleukin-6 induces drug resistance in renal cell carcinoma
Authors: Ishibashi, Kei
Koguchi, Tomoyuki
Matsuoka, Kanako
Onagi, Akifumi
Tanji, Ryo
Takinami-Honda, Ruriko
Hoshi, Seiji
Onoda, Mitsutaka
Kurimura, Yoshimasa
Hata, Junya
Sato, Yuichi
Kataoka, Masao
Ogawa, Soichiro
Haga, Nobuhiro
Kojima, Yoshiyuki
Affiliation: 泌尿器科学講座
Source title: Fukushima Journal of Medical Science
Volume: 64
Issue: 3
Start page: 103
End page: 110
Issue Date: 2018
Abstract: Metastatic renal cell carcinoma (mRCC) is a tumor entity with poor prognosis due to limited therapy options. Tyrosine kinase inhibitors (TKIs), the novel targeted agents have been used for the treatment of mRCC and have shown efficacy. Interferon (IFN)-α is also one of the most frequently used agents in immunotherapy. However, drug resistance needs to be overcome to achieve a sufficiently positive effect. Interleukin-6 (IL-6), which induce suppressor of cytokine signaling-3 (SOCS3) expression, is one of the factors associated with poor prognosis of patients with renal cell carcinoma (RCC). To analyze the influence of IL-6 in drug resistance of RCC, anti-IL-6 receptor antibody was used in combination with IFN or TKIs. The SOCS3 mRNA expression level was significantly increased by IFN-α stimulation in 786-O RCC cells which were resistant to IFN, but not in ACHN cells that were sensitive to IFN. The overexpression of SOCS3 by gene transfection in ACHN significantly inhibited the growth-inhibitory effect of IFN-α. An in vivo study demonstrated that co-administration of SOCS3-targeted siRNA promoted INF-α-induced cell death and growth suppression in 786-O cell xenograft. SOCS3 could be a key component in the resistance to interferon treatment of renal cell carcinoma. Because SOCS3 is rapidly up-regulated by IL-6 and a negative regulator of cytokine signaling, IL-6 expression on RCC cells was also analyzed and the 786-O cells showed the high level of IL-6 mRNA expression under the condition of interferon stimulation. IL-6R antibody, tocilizumab, significantly suppressed cell proliferation in 786-O cells by interferon stimulation accompanied with phosphorylation of STAT1 and inhibited SOCS3 expression. The in vivo effects of combination therapy with tocilizumab and interferon showed significant suppression of 786-O tumor growth in a xenograft model. We also hypothesized that TKI resistance and IL-6 secretion are causally connected. And we found that 786-O RCC cells secrete high IL-6 levels after low dose stimulation with the TKIs sorafenib, sunitinib and pazopanib, inducing activation of AKT-mTOR pathway, NFκB, HIF-2α and VEGF expression. Tocilizumab neutralizes the AKT-mTOR pathway activation and results in reduced proliferation. A combination therapy with tocilizumab and TKI suppresses 786-O tumor growth and inhibits angiogenesis in vivo more efficient than TKI alone. Our findings suggest that IL-6 could induce drug resistance on RCC, and combination therapy of IL-6R inhibitors and IFN/TKIs may represent a novel therapeutic approach for RCC treatment.
Publisher: The Fukushima Society of Medical Science
Publisher (Alternative foam): 福島医学会
language: eng
URI: http://ir.fmu.ac.jp/dspace/handle/123456789/705
Full text URL: http://ir.fmu.ac.jp/dspace/bitstream/123456789/705/1/FksmJMedSci_64_p103.pdf
ISSN: 0016-2590
DOI: 10.5387/fms.2018-15
PubMed ID: 30369518
Related Page: https://doi.org/10.5387/fms.2018-15
Rights: © 2018 The Fukushima Society of Medical Science
Appears in Collections:Vol.64 (2018)

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