RRC ID 44217
Author Oguro T, Ishibashi K, Sugino T, Hashimoto K, Tomita S, Takahashi N, Yanagida T, Haga N, Aikawa K, Suzutani T, Yamaguchi O, Kojima Y.
Title Humanised antihuman IL-6R antibody with interferon inhibits renal cell carcinoma cell growth in vitro and in vivo through suppressed SOCS3 expression.
Journal Eur J Cancer
Abstract Interleukin-6 (IL-6), one of the proinflammatory cytokines, is considered to be one of the factors associated with poor prognosis of patients with renal cell carcinoma (RCC). Suppressor of cytokine signalling-3 (SOCS3) is rapidly up-regulated by IL-6 and a negative regulator of cytokine signalling. SOCS3 not only suppresses cytokine-mediated JAK/STAT signalling, but also sustains MAPK pathways. In our study, among the RCC cell lines, IL-6 mRNA expression was the highest in the 786-O cells, which also showed the highest level of SOCS3 mRNA expression under the condition of interferon stimulation. In contrast, ACHN cells had the lowest expression of both IL-6 and SOCS3 mRNA under the same condition. Our study is undertaken to evaluate the effect of humanised antihuman IL-6 receptor (IL-6R) antibody, which completely neutralises IL-6 activity, in RCC cell proliferation and its effect on signalling pathways. IL-6R antibody, tocilizumab, significantly suppressed cell proliferation in 786-O cells with interferon stimulation. Western blot analysis revealed that the tocilizumab enhanced the interferon-induced phosphorylation of STAT1 and inhibited SOCS3 expression and the phosphorylation of both STAT3 and ERK. In contrast, the IL-6 inhibited STAT1 phosphorylation, enhanced STAT3 phosphorylation and accelerated cell proliferation in ACHN cells. The in vivo effects of combination therapy with tocilizumab and interferon showed significant suppression of 786-O tumour growth in a xenograft model. Morphological observation of the tumours revealed the apoptosis, invasion of inflammatory cells and fibrosis. These findings suggest that combination therapy using an antihuman IL-6R antibody with interferon may represent a novel therapeutic approach for the treatment of RCC.
Volume 49(7)
Pages 1715-24
Published 2013-5-1
DOI 10.1016/j.ejca.2012.11.038
PII S0959-8049(12)00957-4
PMID 23274199
MeSH Animals Antibodies, Monoclonal, Humanized / administration & dosage Antibodies, Monoclonal, Humanized / pharmacology* Antineoplastic Combined Chemotherapy Protocols / therapeutic use Blotting, Western Carcinoma, Renal Cell / drug therapy* Carcinoma, Renal Cell / genetics Carcinoma, Renal Cell / pathology Cell Line, Tumor Cell Proliferation / drug effects* Extracellular Signal-Regulated MAP Kinases / metabolism Female Gene Expression Regulation, Neoplastic / drug effects Humans Interferons / administration & dosage Interferons / pharmacology* Interleukin-6 / genetics Interleukin-6 / metabolism Kidney Neoplasms / drug therapy* Kidney Neoplasms / genetics Kidney Neoplasms / pathology Mice Mice, Inbred BALB C Mice, Nude Phosphorylation / drug effects RNA Interference Receptors, Interleukin-6 / genetics Receptors, Interleukin-6 / immunology Receptors, Interleukin-6 / metabolism Reverse Transcriptase Polymerase Chain Reaction STAT1 Transcription Factor / metabolism STAT3 Transcription Factor / metabolism Suppressor of Cytokine Signaling 3 Protein Suppressor of Cytokine Signaling Proteins / genetics* Suppressor of Cytokine Signaling Proteins / metabolism Xenograft Model Antitumor Assays
IF 7.275
Times Cited 24
Human and Animal Cells