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

Mi Ae Lyu, Bokyung Sung, Lawrence H. Cheung, John W. Marks, Bharat B. Aggarwal, Ricardo C.T. Aguiar, Michael G. Rosenblum

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

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-xL) 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-G1 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.

Original languageEnglish (US)
Pages (from-to)1335-1342
Number of pages8
JournalBiochemical Pharmacology
Volume80
Issue number9
DOIs
StatePublished - Nov 1 2010

    Fingerprint

Keywords

  • Apoptosis
  • Diffuse large B-cell lymphoma
  • Fusion toxin
  • Interleukin-6 receptor
  • STAT3

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this