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.

Endoplasmic reticulum stress, its sensor and signalling systems and the role in regulation of gene expression at malignant tumor growth and hypoxia

“…Цей фактор росту судин в умовах гіпоксії діє також як фактор виживан-ня епітеліальних клітин кришталика шляхом збереження сталої експресії протеїну BCL-2, який попереджає транслокацію протеїну BAX із цитозоля до зовнішньої мембрани мітохондрій [60]. Підвищена експресія шапе-рону HSPA5 у багатьох злоякісних новоутво-реннях, який значною мірою визначає також чутливість пухлинних клітин до хіміотерапії, робить його перспективною мішенню для по-шуку нових шляхів протипухлинної терапії [17,61].…”

Triptolide activates unfolded protein response leading to chronic ER stress in pancreatic cancer cells

“…Although GRP78 expression is maintained at low basal levels in major adult organs, it has often been found to be upregulated in cancer cells (2,16,26,34,36). Studies have shown that although the majority of GRP78 resides in the ER lumen, a fraction of it exists as an ER transmembrane protein, with its NH 2 portion in the cytosol.…”

In vivo intratumoral Epstein–Barr virus replication is associated with XBP1 activation and early-onset post-transplant lymphoproliferative disorders with prognostic implications

“…[53][54][55] In our patients, the simultaneous expression of a latency III pattern associated with intratumoral EBV replication seems to detect a subset of heavily immunosuppressed group of patients with lower rates of rejections or graft vs host disease and higher rates of cytomegalovirus reactivations. These patients have significantly lower overall survival rates and shorter time to develop lymphomas.…”