| 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
|
|
WOS Category
|
ONCOLOGY
|
| Resource |
| Human and Animal Cells |
|
