Proteasome inhibitor PS-341 abrogates IL-6 triggered signaling cascades via caspase-dependent downregulation of gp130 in multiple myeloma

Teru Hideshima, Dharminder Chauhan, Toshiaki Hayashi, Masaharu Akiyama, Nicholas Mitsiades, Constantine Mitsiades, Klaus Podar, Nikhil C Munshi, Paul G Richardson, Kenneth C Anderson

Research output: Journal article (peer-reviewed)Journal article

162 Citations (Scopus)

Abstract

Proteasome inhibitor PS-341 is one of the most promising novel agents against multiple myeloma (MM). We have previously shown that PS-341 inhibits IL-6 triggered phosphorylation of extracellular signal-regulated kinases (ERK) 1/2 (also known as p42/44 mitogen-activated protein kinases) in MM cells. In this study, we further examined whether clinically achievable concentrations of PS-341 could inhibit IL-6 triggered signaling cascades in MM. We found that PS-341 inhibited not only ERK, but also signal transducers and activators of transcription (STAT) 3 as well as Akt phosphorylation. Since gp130 (CD130) dimerizes and is phosphorylated after IL-6 binding to gp80 (IL-6 receptor), we hypothesized that gp130 could be involved in PS-341-induced blockade of signaling cascades mediating MM cell growth, survival, and drug resistance in the bone marrow (BM) microenvironment. In this study, we first demonstrate that PS-341 induces downregulation of gp130 in a time- and dose-dependent manner in vitro, prior to MM cell death. Conversely, downregulation of gp130 is completely abrogated by the pan-caspase inhibitor Z-VAD-FMK, suggesting that downregulation of gp130 is mediated via caspase activation. Z-VAD-FMK also abrogates the inhibitory effect of PS-341 on IL-6-triggered signaling cascades. Importantly, we demonstrate that phosphorylation of ERK, STAT3, and Akt in MM.1S cells induced by either exogenous IL-6 or by binding of MM cells to BM stromal cells is abrogated by PS-341. These studies, therefore, define another novel mechanism whereby PS-341 can overcome the growth and survival advantage in MM cells conferred by the BM milieu. Importantly, this effect on cytokine-induced gp130 signaling cascades may account, at least in part, for the remarkable preclinical sensitivity and clinical responses achieved in MM with PS-341 treatment.

Original languageEnglish
Pages (from-to)8386-8393
Number of pages8
JournalOncogene
Volume22
Issue number52
DOIs
Publication statusPublished - 20 Nov 2003
Externally publishedYes

Keywords

  • Boronic Acids/metabolism
  • Bortezomib
  • Caspases/metabolism
  • Contactins
  • Cysteine Endopeptidases/metabolism
  • Down-Regulation
  • Humans
  • Interleukin-6/metabolism
  • Multienzyme Complexes/metabolism
  • Multiple Myeloma/metabolism
  • Neural Cell Adhesion Molecules/metabolism
  • Proteasome Endopeptidase Complex
  • Pyrazines/metabolism
  • Signal Transduction/physiology

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