The Hsp90 inhibitor IPI-504 overcomes bortezomib resistance in mantle cell lymphoma in vitro and in vivo by down-regulation of the prosurvival ER chaperone BiP/Grp78

Abstract

IntroductionMantle cell lymphoma (MCL) represents ϳ 5%-10% of all nonHodgkin lymphomas. It is characterized by the expansion of mature B-clonal lymphocytes harboring the t(11;14)(q13;q32) translocation, which induces overexpression of cyclin D1, and consequent cell cycle deregulation. In addition, MCL tumor cells carry a high number of secondary chromosomal and molecular alterations affecting proteins involved in cell cycle progression, senescence, and cellular response to DNA damage. 1 The prognosis for this disease is in most cases extremely poor, with a median survival of 5-7 years. 2 Conventional chemotherapeutic regimens have been the standard treatment of MCL. However, all these strategies are rapidly confronted with the onset of resistance, and allogenic bone marrow transplantation represents the only potential curative approach in young patients. 3 Recently, new therapeutic approaches have been entered into the clinic, and the proteasome inhibitor bortezomib was approved for the treatment of relapsed/refractory MCL. 4 Bortezomib induces a p53-independent cytotoxicity, mediated by the proapoptotic BH3-only protein NOXA, and the generation of reactive oxygen species in MCL cells. 5 Further studies have shown a synergism between bortezomib and the BH3-mimetics, obatoclax and ABT-737, highlighting the relevance of NOXA induction to counteract the protective effect of MCL-1 accumulation in proteasomecompromised cells. 6,7 Hypotheses to explain how MCL cells can acquire resistance to bortezomib include the overexpression and/or accumulation of antiapoptotic BCL-2 proteins, the rise of a bortezomib-resistant nuclear factor-B activity, and an increased proteasomal activity. [8][9][10] Despite these studies, the precise mechanism by which bortezomib-resistant MCL cases could lose the capacity to undergo NOXA-mediated mitochondrial apoptosis remains unclear.A key defect might reside within the endoplasmic reticulum (ER) stress pathway, because its activation in MCL cells exposed to bortezomib has been recently shown to elicit NOXA transcription. 11 ER homeostasis is controlled by the immunoglobulin heavy chain binding protein (BiP), also referred as 78-kDa glucose-regulated protein (Grp78). BiP/Grp78 forms a large multiprotein complex with a set of other ER molecular chaperones, including the heat shock protein of 90 kDa (Hsp90) ER homolog, Grp94, protein disulfide isomerase, calcium binding protein, and cyclophilin B. 12 Under nonstressed conditions, BiP/Grp78 binds to and maintains in an inactive monomeric state the ER transmembrane PKR-like ER kinase, inositol requiring protein 1 (IRE1), and the bZIP activating transcription factor 6. 13,14 After proteasome inhibition, the accumulation of polyubiquitinated and misfolded proteins within the ER lumen leads to BiP/Grp78 dissociation from the luminal domains of these sensor proteins, leading to the initiation of the unfolded protein response (UPR): the cytosolic domain of activating transcription factor 6 is cleaved, enabling the protein to translocate and to activ...

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

“…Moreover, we have demonstrated that after bortezomib treatment BiP/GRP78 is induced in the bortezomib-resistant cell lines OCI-LY8 and SUDHL-4, as well as in multiple myeloma and mantle cell lymphoma. 12,48 The selective inhibition of BiP/GRP78 by siRNA significantly overcomes the constitutive resistance to bortezomib and enhances cell toxicity in response to proteasome inhibition, suggesting an important role for BiP/ GRP78 in the mechanisms of response to bortezomib. Moreover, some treatments, such as vomitoxin and epigallocatechin gallate, may reduce BiP/GRP78 transcription 49 and can be used to increase bortezomib cytotoxicity.…”

“…6,9,10 The inhibition of proteasome may have sensitized the DLBCL cells to the cytotoxic action of the chemotherapy. Other- wise, bortezomib exhibits NF-B-independent cytotoxicity in a wide range of different tumor types 48,[51][52][53] and affects many additional pathways that may be differently used by ABC and GCB subtypes. 54 For the first time in the literature we describe the prognostic impact of BiP/GRP78 expression in a homogenous series of DLBCL, all treated with R-CHOP, with a mean follow-up of 2.9 years.…”

A novel combination treatment for breast cancer cells involving BAPTA-AM and proteasome inhibitor bortezomib

“…A previous study revealed that there was an association between loss of sensitivity to the proteasome inhibitor and upregulation of the prosurvival chaperone GRP78 in mantle cell lymphoma samples and cell lines (23). In addition, Kern et al (24) indicated that bortezomib-resistant solid tumor PC-3 and HRT-18 cell lines were capable of secreting high amounts of GRP78.…”

Homeostatic unbalance via HSPA5 gene expression in HepG2/C3A cells exposed to ?-tomatine

“…Such dissociation generates a potent transcription factor for UPR gene expression activating signaling pathways to maintain homeostasis (HOTAMISLIGIL, 2010;PFAFFENBACH;TODD;GLIMCHER, 2008). Induced HSPA5 has been used as possible activation markers of the antiapoptotic and antiproliferative agents in tumor cells creating a mechanism of resistance (KIM et al, 2006;LIU et al, 2007;MILOSZEWSKA et al, 2010;ROSATI et al, 2010;ROUE et al, 2011;TAN et al, 2011). On the other hand, the induction of anti-HSPA5 functions as an apoptotic protein, forming caspase 7 and 12 complexes, keeping them inactive and blocking their proapoptotic function (REDDY et al, 2003).…”