Elevated expression of APE1/Ref-1 and its regulation on IL-6 and IL-8 in bone marrow stromal cells of multiple myeloma

Clin Lymphoma Myeloma Leuk. 2010 Oct;10(5):385-93. doi: 10.3816/CLML.2010.n.072.


A number of growth factors secreted by bone marrow stromal cells (BMSCs), including interleukin-6 and -8 (IL-6/8), are important for the initiation and progression of multiple myeloma (MM). However, the mechanisms that regulate the production of IL-6/8 by BMSC have not yet been well characterized. Human dual functional protein apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) is essential for cell survival and proliferation. Previous studies showed that APE1/Ref-1 was overexpressed in tumor cells, but few studies showed its expression in supportive cells in the tumor microenvironment. We first detected APE1/Ref-1 expression in BMSCs of normal, initial, and recurrent MM patients, and then explore the correlation between APE1/Ref-1 level and IL-6/8 secretion of BMSCs. A marked increase of APE1/Ref-1 expression and abnormal subcellular distribution were observed in MM BMSCs. APE1/Ref-1 overexpression was related to higher secretary level of IL-6/8 by MM BMSCs and the IL-6/8 secretion was blocked significantly by adenovirus-mediated APE1/Ref-1-specific (small interfering RNA) siRNA. Our results also demonstrated that APE1/Ref-1-specific siRNA significantly inhibited DNA binding activity of AP-1 and nuclear factor-κB (NF-κB), 2 important transcription factors in the regulation IL-6/8 secretion in MM BMSCs. The results provided by the present study indicate APE1/Ref-1, which plays a regulatory role in IL-6/8 production by BMSCs, may be a potential therapeutic target of MM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / pathology
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / biosynthesis*
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / genetics
  • Female
  • Humans
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism*
  • Male
  • Middle Aged
  • Multiple Myeloma / genetics
  • Multiple Myeloma / metabolism*
  • Multiple Myeloma / pathology
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / genetics
  • Stromal Cells / metabolism
  • Stromal Cells / pathology


  • Interleukin-6
  • Interleukin-8
  • RNA, Small Interfering
  • APEX1 protein, human
  • DNA-(Apurinic or Apyrimidinic Site) Lyase