The rGel/BLyS fusion toxin inhibits STAT3 signaling via down-regulation of interleukin-6 receptor in diffuse large B-cell lymphoma

Biochem Pharmacol. 2010 Nov 1;80(9):1335-42. doi: 10.1016/j.bcp.2010.07.017. Epub 2010 Jul 21.


Aberrant signal transducer and activator of transcription (STAT)3 signaling participates in the development and progress of human cancers. We previously generated a highly cytotoxic fusion toxin designated rGel/BLyS for receptor-mediated delivery of the rGel toxin to malignant B-cells. In this study, we examined this fusion toxin for its ability to impact STAT3 signaling in diffuse large B-cell lymphoma (DLBCL). The activated B cell-like DLBCL lines were found to express higher levels of interleukin-6 receptor (IL-6R) and STAT3 than did the germinal center B cell-like DLBCL lines. Treatment of DLBCL cells with rGel/BLyS resulted in down-regulation of IL-6R and inhibited STAT3 phosphorylation, STAT3-DNA binding activity, and IL-6-inducible STAT3 reporter gene activity. In agreement with these results, we additionally found that rGel/BLyS down-regulated levels of several STAT3 targets (c-Myc, p21, Mcl-1, and Bcl-x(L)) and p-SYK, a positive regulator of STAT3. Inhibition of IL-6R-mediated STAT3 signaling by rGel/BLyS led to growth inhibition, triggered accumulation of cells in the sub-G(1) phase of the cell cycle, and induced apoptosis. Our results indicate that rGel/BLyS is an excellent candidate for the treatment of aggressive DLBCL which is resistant to conventional chemotherapeutic regimens and STAT3 signaling pathway may be an attractive therapeutic target for non-Hodgkin's lymphoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • B-Cell Activating Factor / pharmacology*
  • Cell Line, Tumor
  • DNA / metabolism
  • Down-Regulation
  • G1 Phase / drug effects
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lymphoma, Large B-Cell, Diffuse / drug therapy*
  • Lymphoma, Large B-Cell, Diffuse / metabolism
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Interleukin-6 / antagonists & inhibitors*
  • Recombinant Fusion Proteins / pharmacology*
  • Ribosome Inactivating Proteins, Type 1 / pharmacology*
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects*
  • Syk Kinase


  • B-Cell Activating Factor
  • Intracellular Signaling Peptides and Proteins
  • Receptors, Interleukin-6
  • Recombinant Fusion Proteins
  • Ribosome Inactivating Proteins, Type 1
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • GEL protein, Gelonium multiflorum
  • DNA
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • Proto-Oncogene Proteins c-akt