Suppressor of cytokine signaling-1 expression by infectivity-enhanced adenoviral vector inhibits IL-6-dependent proliferation of multiple myeloma cells

M. Yamamoto, N. Nishimoto, J. Davydova, T. Kishimoto, D. T. Curiel

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Multiple myeloma (MM) accounts for 10% of hematological malignant disorders. Its refractory nature indicates the necessity of developing novel therapeutic modalities. Since interleukin 6 (IL-6) is one of the major growth factors for MM cells, we expressed suppressor of cytokine signaling-1 (SOCS-1), one of the blockades of IL-6 receptor downstream signaling, to suppress the proliferation of MM cells. Because MM cells are resistant to conventional adenoviral vector infection, we utilized infectivity-enhanced adenoviral vectors with an RGD4C motif in the adenoviral fiber-knob region (RGD-modified vector). In infectivity analysis, RGD-modified vectors were superior to unmodified controls in the majority of the MM cell lines tested. The overexpression of SOCS-1 using infectivity-enhanced adenoviral vectors achieved growth suppression in IL-6-dependent MM cells, but not in the IL-6-independent cells. IL-6-induced STAT3 phosphorylation was suppressed in IL-6-dependent cells, indicating that the signal transduction cascade of the IL-6 receptor signaling was blocked. In aggregate, SOCS-1 overexpression with RGD-modified adenoviral vectors achieved the antiproliferative effect in IL-6-dependent MM cells. These results provide an initial proof-of-principle of the anticancer effect of SOCS-1 expression vector as well as a promise for the future development of therapeutic modality for MM based on this vector.

Original languageEnglish (US)
Pages (from-to)194-202
Number of pages9
JournalCancer gene therapy
Volume13
Issue number2
DOIs
StatePublished - Feb 2006
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported in part by the National Organization for Rare Disorders, Research Grant Program for Multiple Myeloma to Masato Yamamoto, and by a Grant-in-Aid of the Ministry of Health, Labor and Welfare of Japan to Norihiro Nihsimoto. We thank Dr Victor Krasnykh for providing the Ad backbone plasmid for infectivity-enhanced vectors, and Dr Kazuyuki Yoshizaki and Long Le for excellent advice.

Keywords

  • Adenoviral vector
  • IL-6
  • Infectivity enhancement
  • Myeloma
  • Proliferation
  • SOCS

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