Expression and release of glucose-regulated protein-78 (GRP78) in multiple myeloma
Normann Steiner1,2, Bojana Borjan2,3, Roman Hajek4,5
1Department of Internal Medicine V, Hematology and Medical Oncology, Innsbruck Medical University, Innsbruck, Austria.
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.
Insights
Glucose-regulated protein 78 kDa (GRP78/BiP) expression and release are not reliable biomarkers for distinguishing multiple myeloma (MM) stages. Further research is needed to identify effective diagnostic markers for MM progression.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Multiple myeloma (MM) is a largely incurable plasma cell neoplasm.
- Acquired treatment resistance contributes to MM incurability.
- Glucose-regulated protein 78 kDa (GRP78/BiP) is an endoplasmic reticulum (ER) chaperone involved in protein folding and stress responses.
Purpose of the Study:
- To evaluate the expression and release of GRP78/BiP in different stages of multiple myeloma.
- To determine if GRP78/BiP can serve as a biomarker to differentiate between monoclonal gammopathy of undetermined significance (MGUS), newly diagnosed MM (NDMM), and relapsed/refractory MM (RRMM).
Main Methods:
- Quantified GRP78 protein expression and plasma levels in bone marrow aspirates from MGUS, NDMM, and RRMM patients using immunohistochemistry and ELISA.
- Investigated GRP78 release and processing in MM cell lines under various stress conditions (acidosis, ER stress, apoptosis, necrosis).
Main Results:
- GRP78 protein expression in the ER and on the cell surface showed no significant differences between MGUS, NDMM, and RRMM patients.
- A trend towards higher surface GRP78 expression was observed in RRMM.
- Released GRP78 protein levels in bone marrow plasma did not significantly increase across patient groups.
- MM cells released full-length GRP78 under apoptosis but only proteolytic fragments under necrosis, acidosis, or ER stress.
Conclusions:
- Ectopic GRP78 expression on the cell membrane is not a suitable marker for distinguishing MGUS from NDMM and RRMM.
- GRP78 release into the microenvironment is also not a reliable biomarker for differentiating these MM stages.
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