The expression of the endoplasmic reticulum stress sensor BiP/GRP78 predicts response to chemotherapy and determines the efficacy of proteasome inhibitors in diffuse large b-cell lymphoma.

Abstract	Activation of the endoplasmic reticulum (ER) stress pathway is associated with poor response to doxorubicin-containing regimens, such as rituximab, cyclophosphamide, hydroxydaunorubicin (doxorubicin), vincristine and prednisone (R-CHOP), in patients with diffuse large B-cell lymphoma (DLBCL). Bortezomib, a proteasome inhibitor, interferes with ER responses and improves survival in patients with aggressive hematologic malignant tumors, although its use in DLBCL patients remains controversial. The 78-kDa glucose-regulated protein (GRP78), also known as immunoglobulin heavy chain binding protein (BiP), is an ER stress sensor involved in the resistance to doxorubicin and bortezomib, but its role in the response to chemotherapy in DLBCL has not been explored before. We show that high BiP/GRP78 expression is related to worse overall survival (median overall survival, 5.2 versus 3.4 years). Moreover, cell death after R-CHOP in DLCBL cell lines is associated with decreased BiP/GRP78 expression. Conversely, DLBCL cell lines are primarily resistant to bortezomib, probably owing to BiP/GRP78 overexpression. Small-interfering RNA silencing of BiP/GRP78 renders all cell lines sensitive to bortezomib. R-CHOP with bortezomib (R-CHOP-BZ) reduces BiP/GRP78 expression and overcomes bortezomib resistance, mimicking the small-interfering RNA silencing of BiP/GRP78. Accordingly, R-CHOP-BZ is the most effective treatment, providing a rationale for the use of this combinational therapy to improve DLBCL patient survival. Moreover, this study provides preclinical evidence that the germinal center B-cell-like subtype DLBCL is sensitive to bortezomib combined with immunochemotherapy.
Authors	Ana Mozos, Gaël Roué, Armando López-Guillermo, Pedro Jares, Elias Campo, Dolors Colomer, Antonio Martinez
Journal	The American journal of pathology (Am J Pathol) Vol. 179 Issue 5 Pg. 2601-10 (Nov 2011) ISSN: 1525-2191 [Electronic] United States
PMID	21907693 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright	Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Chemical References	Boronic Acids Endoplasmic Reticulum Chaperone BiP GRP8 protein, human HSPA5 protein, human Protease Inhibitors Pyrazines RNA, Messenger RNA, Small Interfering Receptors, Neuropeptide Vincristine Bortezomib Doxorubicin Cyclophosphamide Prednisone
Topics	Adolescent Adult Aged Aged, 80 and over Antineoplastic Combined Chemotherapy Protocols (administration & dosage, therapeutic use) Boronic Acids (administration & dosage) Bortezomib Cell Line, Tumor Cyclophosphamide (administration & dosage) Down-Regulation Doxorubicin (administration & dosage) Drug Resistance, Neoplasm Endoplasmic Reticulum Chaperone BiP Female Humans Lymphoma, Large B-Cell, Diffuse (drug therapy) Male Middle Aged Prednisone (administration & dosage) Protease Inhibitors (therapeutic use) Pyrazines (administration & dosage) RNA, Messenger (metabolism) RNA, Small Interfering (physiology) Receptors, Neuropeptide (metabolism) Survival Analysis Treatment Outcome Unfolded Protein Response (drug effects) Vincristine (administration & dosage) Young Adult

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