Abstracts (complete list) - Wissenschaft Online

Silke Meister, Kirsten Neubert, Kai Herrmann, Renate Burger, Martin Gramatzki,
Sabine Hahn, Sandra Schreiber, Ulrich Schubert, Hans-Martin Jäck, Reinhard Voll
Extensive immunoglobulin production sensitizes myeloma
cells for proteasome inhibition
Multiple myeloma (MM), an incurable plasma cell neoplasia, is characterized by
overproduction of monoclonal immunoglobulins (Ig). The recently clinically approved
proteasome inhibitor bortezomib (Bz) acts directly on MM cells to cause cell death,
supposedly by blocking the antiapoptotic factor NF-κB. However, the exact mechanism
by which Bz acts is still under investigation. Extensive synthesis of Ig in MM cells results
also in defective ribosomal products (DRiPs) and unfolded proteins degraded by the
proteasome. Therefore, we hypothesized that the proapoptotic effect of Bz is due to the
accumulation of unfolded proteins and DRiPs along with inhibition of NF-κB. Using the
human MM IgG-secreting cell line JK-6L and murine •H-chain-transfected Ag8.H
myeloma cells, proteasome inhibitor treatment induced markedly more apoptotic cell
death in subclones producing high compared to low amounts of Ig. Unexpectedly,
bortezomib did not markedly alter NF-κB activity. In contrast, Ig positive MM cells
showed a highly induced AP-1 DNA binding activity upon Bz treatment. Importantly, in
Ig-high MM cells Bz triggered production of reactive oxygen species (ROS) as well as
strong activation of endoplasmic reticulum (ER) stress components involved in apoptosis
such as CHOP and caspases. Additionally, cells harbouring Ig showed enhanced
expression of the proapoptotic factor Bax and reduced expression of the antiapoptotic
protein Bcl-2 due to Bz treatment. Moreover, proteasome inhibition results in formation
and accumulation of IgG-derived DRiPs. Hence, we conclude that proteasome inhibition
preferentially affects cells producing high amounts of proteins. Bz-induced cell death in
MM cells is most likely mediated by ER stress induced through accumulation of unfolded
proteins/DRiPs.