Oncotarget

Research Papers:

Expression and release of glucose-regulated protein-78 (GRP78) in multiple myeloma

Normann Steiner _, Bojana Borjan, Roman Hajek, Karin Jöhrer, Georg Göbel, Wolfgang Willenbacher, Johann Kern, Eberhard Gunsilius and Gerold Untergasser

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Oncotarget. 2017; 8:56243-56254. https://doi.org/10.18632/oncotarget.17353

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Abstract

Normann Steiner1,2,*, Bojana Borjan2,3,*, Roman Hajek5,6, Karin Jöhrer3, Georg Göbel4, Wolfgang Willenbacher1, Johann Kern3, Eberhard Gunsilius1,2,* and Gerold Untergasser1,3,*

1Department of Internal Medicine V, Hematology and Medical Oncology, Innsbruck Medical University, Innsbruck, Austria

2Laboratory for Tumor Biology and Angiogenesis, Innsbruck Medical University, Innsbruck, Austria

3Tyrolean Cancer Research Institute, Innsbruck, Austria

4Department of Medical Statistics, Informatics and Health Economics, Innsbruck Medical University, Innsbruck, Austria

5Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic

6Department of Hemato-Oncology, University Hospital Ostrava, Ostrava, Czech Republic

*These authors have contributed equally to this work

Correspondence to:

Normann Steiner, email: [email protected]

Keywords: multiple myeloma, MGUS, GRP78, ELISA, prognostic marker

Received: January 17, 2017     Accepted: April 11, 2017     Published: April 21, 2017

ABSTRACT

Introduction: Multiple myeloma (MM) is a plasma cell neoplasm that is mostly incurable due to acquired resistance during the treatment course. Thus, we evaluated expression and release of glucose-regulated protein 78 kDa (GRP78/BiP), an endoplasmic reticulum (ER) based pro-survival chaperone involved in immunoglobulin folding and unfolded protein responses.

Results: GRP78 protein expression in the ER and on the cell surface did not significantly differ between MGUS, NDMM and RRMM patients although there was a trend to higher surface expression in RRMM. In bone marrow plasma, the amount of released GRP78 protein was not significantly increased between MGUS-, NDMM- and RRMM patients. MM cells of the three cell lines release GRP78 as full-length protein under apoptotic, but not under acidotic or ER-stress conditions. In necrosis, only proteolytic fragments of GRP78 were detected in supernatants of MM cells.

Materials and Methods: GRP78 protein expression and plasma levels were quantified in bone marrow aspirates of patients with monoclonal gammopathy of undetermined significance (MGUS, n = 29), newly diagnosed MM (NDMM, n = 29) and with relapsed/refractory MM (RRMM, n = 15) by immunohistochemistry and sandwich ELISA. The human MM cell lines U266, NCI-H929 and OPM-2 were used for functional GRP78 release- and processing studies after induction of acidosis, ER stress, apoptosis and necrosis.

Conclusions: Ectopic expression of GRP78 on cell membrane or its release in the microenvironment is not a suitable marker to distinguish MGUS from NDMM and RRMM.


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