title: Humanised antihuman IL-6R antibody with interferon inhibits renal cell carcinoma cell growth in vitro and in vivo through suppressed SOCS3 expression.
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.
authors.affiliation: Department of Urology, Fukushima Medical University, Fukushima, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Oguro
authors.forename: Kei
authors.initials: K
authors.lastname: Ishibashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Sugino
authors.forename: Koichi
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Shintaro
authors.initials: S
authors.lastname: Tomita
authors.forename: Norio
authors.initials: N
authors.lastname: Takahashi
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Yanagida
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Haga
authors.forename: Ken
authors.initials: K
authors.lastname: Aikawa
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Suzutani
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamaguchi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Kojima
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007372:Interferons / Q000008:administration & dosage / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; C106644:SOCS3 protein, human; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007372:Interferons; D048049:Extracellular Signal-Regulated MAP Kinases; C502936:tocilizumab