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Preserved proteasome inhibition capacity which initiates a potent unfolded protein response (UPR) is not sufficient for the antimyeloma activity of bortezomib 

Yossi Cohen1, Osnat Garach-Jehoshua2, Odit Gutwein1, Adina Bar-Haim3 and Abraham Kornberg1

1Department of Hematology, 2Hematology Laboratory and 3Chemistry Department, Assaf Harofeh Medical Center, Zerifin, Israel. Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Israel
Running title: UPR is not predictive for the activity of bortezomib
Corresponding author: 
Dr Yossi Cohen, MD, BsC.  HYPERLINK "mailto:yosefc@asaf.health.gov.il" yosefc@asaf.health.gov.il
Department of Hematology, Assaf Harofeh Medical Center, Zerifin 70300, Israel. 
Tel: +972 8 9778223, Fax: +972 8 9779772

Keywords: multiple myeloma, gene expression profile, proteasome, MMP12, heat shock proteins
Number of words in the abstract: 216, in the manuscript: 2297 
All authors declare no conflict of interests
Abstract
Background and Objective: One of the insults of proteasome inhibition is initiation of the endoplasmic reticulum (ER) stress response among a diversity of molecular changes. The end result of the former event is however complex because initially it protects the cells from accumulated unfolded protein damage by inducing the UPR, accelerating protein degradation and repressing protein synthesis. However overwhelming ER stress activates terminal UPR, leading to apoptosis. 
Methods: In the present work we compared gene expression profile changes in response to bortezomib treatment of cultured bone marrow samples from patients with bortezomib sensitive versus bortezomib resistant myeloma. 
Results:�In both instances bortezomib caused a pronounced induction of >30 heat shock protein transcripts combined with a variable upregulation of several proapoptotic genes (e.g. DDIT3) induced during uncompensated ER stress. Another subset of genes (e.g. MMP12, STAC, PPP1R15A, CCL2, IL1A, IL1B, IL1RA) was induced differently in bortezomib sensitive versus resistant cases. 
Conclusion:�Overall, our results indicate that preserved proteasome inhibition capacity which promotes a potent UPR still not predictive for a favorable clinical response to bortezomib neither the induced chaperone genes confer resistance to the drug. The cytotoxicity of bortezomib might be related then to the differently regulated genes but more reasonably is dependent on post-transcriptional activation of proapoptotic pathways which seem to be ineffective in resistant cases. 

Introduction
Although the novel drug bortezomib (velcade) has become one of the mostly used agents in multiple myeloma (MM), the particular mechanism which executes its cytotoxic effect remains elusive due to the diversity of molecular changes induced by proteasome inhibition. One of the earliest thoughts regarding the mechanism of tumor cell killing induced by bortezomib came from the role of the proteasome in degradation of I�B, the inhibitor of NF�B [1-3]. This explanation however seemed to be unsatisfactory because direct inhibitors of I�B reduced proliferation of MM cells markedly less effectively than bortezomib [4,5]. Bortezomib also caused 20-to-60-fold induction of the proapoptotic gene NOXA in various cancer cells [6] while in other models it impaired tumor growth via inhibition of HIF-1� and repression of HIF-1 transcriptional activity with attenuation of the release of vascular endothelial growth factor (VEGF) [7]. Additional studies suggested that the general accumulation of misfolded proteins in the ER is the major mechanism of action of bortezomib [8,9]. The latter insult initiates the UPR signaling which in turn stimulates splicing of inactive XBP1 [10] whereas spliced XBP1 (XBP1s) regulates genes that are responsible for the ER-associated degradation (ERAD) (e.g. EDEM), ending-up within the proteasome. XBP1s also induces genes which are responsible for protein folding such as p58IPK and a variety of ER chaperones [11]. Although UPR activation can return protein homeostasis and is also essential for plasma cell differentiation and survival by induction of various ER chaperones and folding enzymes [12-15], under prolonged and uncompensated ER stress the UPR promotes cellular apoptosis, known as terminal UPR [15-17]. The latter event is mediated by the proapoptotic transcription factor CHOP (also known as GADD153 and DDIT3), which is induced via PERK and ATF6 pathways. CHOP causes down-regulation of BCL2, thereby leading to caspase-dependent apoptosis [18,19]. In HNSCC cells, bortezomib induced apoptosis through induction of ER stress along with the generation of reactive oxygen species (ROS) which led to caspase activation whereas inhibition of NF-kappaB was not sufficient to initiate apoptosis [20]. Consistent with the ER stress concept of bortezomib antimyeloma activity, a correlation was found between the levels of immunoglobulin chain production and the sensitivity to proteasome inhibitors in subclones of the human IgG-secreting myeloma cell line JK-6L and in subclones of the murine myeloma cell line Ag8 transfected with an expression plasmid encoding the � heavy (H) chain [21]. Moreover, proapoptotic factors of the ER stress response were induced to a greater extent in subclones producing high levels of �H-chains than in those producing no �H-chains. Conversely, MM cells became bortezomib resistant through inhibition of unfolded protein accumulation by acquired mutations of the PSMB5 gene which prevented the catastrophic ER stress [22]. 
Our present work deals with the cytotoxic mechanisms offered above in the context of authentic MM cells from patients with clinical response versus resistance to bortezomib regimens.  
Methods
Patients: The four MM cases were selected according to their clinical fitness to the study design including extreme bone marrow (BM) infiltration by tumor cells (> 90%), which eliminated the need for cell separation procedures known to interfere with recording of the authentic gene expression profile (GEP) [23,24]. The study was approved by the local institute review boards.
Tissue culture: BM aspirates were collected into heparinized syringes and transferred into vertical tubes for >30 minutes; then the fluid layer above the red blood cell (RBC) sediment was collected and ~ 107 cells (50-300 �l aspiration fluid) were seeded into 24-well plates (BD Falcon� 24-well Multiwell Plate). After > 15 minute incubation (RT) 1 ml RPMI-1640  containing 2 mm l-glutamine (Sigma, Rehovot, Israel), 50 U/ml penicillin, 50 �g/ml streptomycin (Sigma) and 20% (v/v) heat-inactivated fetal bovine serum (Biological Industries, Kibbutz Beit Haemek, Israel) was added to wells. Cells were maintained at 37 �C in a humidified 5% CO2 incubator. Cultures were fed bi-weekly by replacing 70% of the medium with fresh supplement. The bortezomib used was VELCADE� for injection (Janssen-Cilag Ltd). For RNA extraction most of the medium was removed (leaving 200-300 �l) and after a vigorous pippetation the released cells were collected and fixed with liquid nitrogen in ~70 �l fractions. 
RNA extraction: Frozen samples were lysed by adding 300 �l lysis buffer to tubes. RNA was isolated by MagNA Pure Compact RNA Isolation procedure using MagNA Pure Compact instrument (Roche Diagnostics, Ltd, Israel). Integrity of RNA was examined by Agilent 2100 Bioanalyzer. 
GEP: Biotin-labeled cRNA was generated from 200 ng total RNA, hybridized onto GeneChip Human Gene1.0 ST Array (Affymetrix, Santa Clara, CA, USA) and the data was processed with the Affymetrix GeneChip Scanner 3000 and Affymetrix Expression Console. Normalization was done by the RMA method and fold change results were calculated relative to the fresh BM sample of each case. The microarray data was deposit on the public gene expression ominibus (GEO) accession number GSE51940  HYPERLINK "http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE51940" http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE51940




Results and discussion
We analysed BM samples from an overall group of four MM patients, two of which were newly diagnosed (cases A, B) and responded to velcade/dexamethasone (Vel/Dex) induction (Table 1) as opposed to the other two patients who failed velcade regimens, one with newly diagnosed MM (case C) showing primary resistance to Vel/Dex combination as reflected by increase in his paraprotein levels and persistence of > 95% plasma cells in repeated BM examination after 6 injections of velcade (days 1, 4, 8, 11, 29, 32, 36, 39); the second refractory case (case D) was heavily pretreated and initially responded to Vel/Dex with VGPR (very good partial response) followed by long term remission after consolidation stem cell transplantation (SCT) with melphalan 200 mg/m2. However, after almost 3 years the patient progressed and received second line treatment with lenalidomide/dexamethasone (Len/Dex) but was refractory to this regimen, then he partially responded to retreatment with Vel/Dex and continued with 2 salvage cycles of VD-PACE (velcade combined with dexamethasone, platinol, adriamicin, etoposide) and underwent second SCT while in VGPR (case D). Once again after 6 months the patient progressed but now he became totally resistant to bortezomib with no response to Vel/Dex and to VD-PACE (Table 1) as evident by the development of chest wall plasmacytomas, pancytopenia, hypercalcemia, renal failure, sharp increase in his urine paraprotein levels as well as > 95% plasma cells in the BM aspirate and biopsy under treatment. At this stage his BM sample was examined in our present study and the patient entered a clinical trial with carfilzomib, pomalidomide and dexamethasone after which he achieved a PR (partial response), with drop in his paraprotein levels to almost 1/3 of his pretreatment levels and improvement in all of his clinical and laboratory tests including repeated BM biopsy. The four patient characteristics are summarized on Table 1. Velcade was added to the cultured BM samples at a concentration of 2 �g/ml, which was found in our preliminary assessment to kill cultured primary MM cells within 24 hours (data not shown). After 6-8 hour exposure to the drug the treated and control cells were released from the bottom wells and fixed with liquid nitrogen. As compared with the control samples, the GEPs analysed from the treated samples showed dramatic upregulation of a large subset of genes mostly encoding for heat shock protein (HSPs) or related ER stress chaperones and this observation was common to the entire group of 4 patients examined irrespective of their clinical response to bortezomib regimens. The list of the modulated genes is presented on Figure 1 (HSP and related transcripts are marked in yellow). Thus, the in vitro induction of UPR chaperone genes in response to bortezomib by no means heralds clinical response to the drug despite the accumulated literature data which links the antitumor effect of bortezomib with UPR activation [8-10, 17-19]. Of note, a subset bortezomib induced genes was also inducible by direct ERAD inhibitors [25]  (Figure 2) whereas proteasome inhibition likely initiates the UPR via interruption of the final step in the degradation of unfolded proteins [26-29], thus the impressive induction of many ER chaperone genes in the BM samples from our bortezomib resistant cases implies that the clinical inactivity of the drug in those patients did not result from an inaccessible binding site or from an unblcokable proteasome in the tumor cells otherwise no induction of HSP transcripts could be elicited in vitro. Accordingly, the models of impaired drug binding used to explain the mechanism of bortezomib resistance on the basis of acquired resistance in mutant subclones [30-34] might be irrelevant for primary tumor cells as already noticed [35]. In addition, neither NOXA nor HIF-1�, GADD45A, GADD45B, GADD45G, TNFRSF10B, FAS, FASLG, DAP3, CASP8, CASP7 or CASP1, which were reported to promote apoptosis in bortezomib treated cells [36,37], were induced markedly in any of the BM samples examined in our series and no BCL2 repression could be recognized. Furthermore, although the proapoptotic signaling molecule CHOP (DDIT3), which is considered to be induced and activated by ER stress [18,19], was induced to somewhat greater extent in our bortezomib sensitive versus resistant cases, the differences in expression were too small to explain the clinical differences seen. Nevertheless, several other genes were induced much more pronouncedly (e.g., PPP1R15A; see Figure 1) or even solely (e.g., IL1A, IL1B, ADAMDEC1, ALOX5AP, IL1RN, FPR2, C3, IL2RA, CCL22, IL7R, IL10RA) in the BM samples from our bortezomib responsive versus resistant cases, most of which were encoding for chemokine/ cytokine related genes suggesting inflammatory reaction preceding apoptosis. Still, the post induction signal intensities of all of the above genes overlapped the signal intensities recorded from the same genes in the BM samples from our bortezomib refractory cases (despite the lack of induction). Exceptional were MMP12 and STAC which clearly distinguished between bortezomib responsive and bortezomib resistant cases without overlap in the signal intensities. Specifically, in the BM samples which were treated with bortezomib MMP12 became upregulated 6.55 and 18.62 folds in cases A and B, respectively as compared to the corresponding untreated BM samples versus 0.48 and 1.08 folds in cases C and D, respectively while STAC was induced 3.03 and 3.09 folds versus 0.94 and 1.29 folds, respectively. However, the ability of the latter two genes to explain or predict the clinical response to bortezomib requires further assessment in larger cohorts of samples. More reasonably, the lack of clinical response to bortezomib regimens in our bortezomib refractory cases was due to post proteasome blockade failure to activate the optional proapoptotic pathway e.g. p38 and ATF6 [38], Bax and Bak [39], generation of reactive oxygen species (ROS) [40,41], disregulation of the intracellular calcium [42] or as yet unrecognized proteasome related proapoptotic pathway. 

Within the limitations of our results the first issue to be considered is the differences in the drug exposure in vitro versus in vivo. In this study the bortezomib concentration added to cultures was much higher (~20 folds) than the usual peak plasma levels (89-120 ng/ml). However, bortezomib is rapidly and widely distributed to tissues and the mean 24-hour total radioactivity levels (TR) of 14C-bortezomib was found to be 43.5, 30.5 and 27.8 folds higher in the BM versus plasma of Sprague-Dawley rats after the first, third and fourth dose of the drug in a biweekly schedule, respectively [43]. Likewise, the area under the concentration-time curve (AUC; �g-eq. h/g) of TR between 0 and 72 hours post 14C-bortezomib injection (AUC0-72 h) was 31.7 and 24.1 folds higher in the BM versus plasma after the first and the fourth dose, respectively. Therefore, it seems reasonable that the bortezomib concentration used here in vitro is also reachable in the BM but to study the in vivo influence of bortezomib on the GEP of the tumor cells directly we are now comparing the GEPs in fresh BM samples from patients shortly after injection of the drug. In the future it will be also necessary to exclude dissociation between transcription and translation of relevant transcripts. In the present study we also did not check for the differences in proapoptotic markers owing to the limited number of available BM cells as well as the extreme variability in survival duration of primary MM cells in our culture model [24]. 
Conclusions
Our comparative GEP which was analysed from BM samples of patients with bortezomib responsive versus bortezomib resistant myeloma following in vitro exposure to the drug adds complementary information to prior GEP comparisons of unmanipulated BM samples; the latter principally provided response and survival classifiers [44]. Our main finding was the observation that preserved proteasome inhibition capacity (as evident from the potent UPR induction) is by itself not sufficient neither predictive for the antimyeloma activity of bortezomib. On the other hand, the excellent clinical response to bortezomib regimens despite the marked induction of numerous HSP transcripts in the BM samples from our bortezomib responsive cases (Figure 1) raised doubts about the role attributed to HSP on bortezomib resistance or on the expectations from HSP inhibitors to overcome drug resistance [38, 45-46], though direct ERAD inhibitors might synergized with bortezomib [47].
Clinical practice points
The lack of clinical response to bortezomib regimens despite the preserved proteasome inhibition capacity as evident by induction of a potent UPR following exposure to the drug in vitro indicates that bortezomib resistance is not necessarily related to failure of proteasome blockade. To evaluate this issue directly we are comparing now the GEP in BM samples from patients 1-hour after the first infusion of the drug and if there will be significant differences in expression of the UPR transcripts between bortezomib responsive and resistant cases it will give rational for the assessments of higher doses of bortezomib in resistant cases in order to overcome possible suboptimal concentration of the drug or some interference to its binding to its target sight in vivo while if there will be no difference this will strengthen the assumption that the resistance is indeed related to post proteasome blockade failure to activate the optional proapoptotic pathways.  





Acknowledgments
The authors thank Relly Forer (PhD), Inna Vulin (PhD) and Dina Volodarsky (MsC) from Dyn diagnostics Ltd for professional microarray and Bioinformatic service, Izhar Hardan (MD) from Meir hospital for support and advices and to Dov Zipory (PhD) from the Weizmann Institute of Science for the training and advices.
Author�s contribution
Y.C. created and designed research, performed research, collected and analyzed data and wrote the paper; all authors assisted in recruitment of patients, technical assist, advices and gave final approval of the manuscript for publication.











References
Alkalay I, Yaron A, Hatzubai A, Jung S, Avraham A et al. (1995) In vivo stimulation of I kappa B phosphorylation is not sufficient to activate NF-kappa B. Mol Cell Biol 15: 1294-1301. 
Alkalay I, Yaron A, Hatzubai A, Orian A, Ciechanover A, et al (1995) Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A.92: 10599-10603.
Kanarek N, London N, Schueler-Furman O, Ben-Neriah Y (2010) Ubiquitination and degradation of the inhibitors of NF-kappaB. Cold Spring Harb Perspect Biol 2: a000166.
Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Richardson PG, et al. (2002) Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: therapeutic applications. Blood 99: 4079-4086.
Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, et al. (2002) NF-kappa B as a therapeutic target in multiple myeloma. J Biol Chem 277: 16639-16647.
Fern�ndez Y, Verhaegen M, Miller TP, Rush JL, Steiner P, et al. (2005) Differential regulation of noxa in normal melanocytes and melanoma cells by proteasome inhibition: therapeutic implications. Cancer Res 65: 6294-6304.
Befani CD, Vlachostergios PJ, Hatzidaki E, Patrikidou A, Bonanou S, et al. (2012) Bortezomib represses HIF-1� protein expression and nuclear accumulation by inhibiting both PI3K/Akt/TOR and MAPK pathways in prostate cancer cells. J Mol Med (Berl) 90: 45-54.
Nawrocki ST, Carew JS, Pino MS, Highshaw RA, Dunner K Jr, et al. (2005) Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis.�Cancer Res 65: 11658�11666.
Nawrocki ST, Carew JS, Dunner K Jr, Boise LH, Chiao PJ, et al. (2005) Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells.�Cancer Res�65: 11510�11519.
Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107: 881-891.
Lee AH, Iwakoshi NN, Glimcher LH (2003) XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol 23: 7448-7459.
Iwakoshi NN, Lee AH, Glimcher LH (2003) The X-box binding protein-1 transcription factor is required for plasma cell differentiation and the unfolded protein response. Immunol Rev 194: 29-38.
Reimold AM, Iwakoshi NN, Manis J, Vallabhajosyula P, Szomolanyi-Tsuda E, et al. Plasma cell differentiation requires the transcription factor XBP-1 (2001) Nature 412: 300-307.
Iwakoshi NN, Lee AH, Vallabhajosyula P, Otipoby KL, Rajewsky K, et al. (2003) Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat Immunol 4: 321-329.
Gass JN, Gifford NM, Brewer JW (2002) Activation of an unfolded protein response during differentiation of antibody-secreting B cells. J Biol Chem 277: 49047�49054.
Kim R, Emi M, Tanabe K, Murakami S (2006) Role of the unfolded protein response in cell death. Apoptosis 11: 5�13.
Sano R, Reed JC. ER stress-induced cell death mechanisms (2013) Biochim Biophys Acta 1833: 3460-3470.
McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ (2001) Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol 21: 1249-1259.
Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D (2000) Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5: 897-904.
Fribley A, Zeng Q, Wang CY (2004) Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells.�Mol Cell Biol 24: 9695�9704.
Meister S, Schubert U, Neubert K, Herrmann K, Burger R, et al. (2007) Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. Cancer Res 67: 1783-1792.
Ri M, Iida S, Nakashima T, Miyazaki H, Mori F, et al. (2010) Bortezomib-resistant myeloma cell lines: a role for mutated PSMB5 in preventing the accumulation of unfolded proteins and fatal ER stress. Leukemia 24: 1506-1512.
Cohen Y, Garach-Jehoshua O, Bar-Chaim A, Kornberg A (2012) Niche-modulated and niche-modulating genes in bone marrow cells. Blood Cancer J 14: 2:e97.
Cohen Y, Gutwein O, Garach-Jehoshua O, Bar-Haim A, Kornberg A (2013) The proliferation arrest of primary tumor cells out-of-niche is associated with widespread downregulation of mitotic and transcriptional genes. Hematology: in print.
Wang Q, Shinkre BA, Lee JG, Weniger MA, Liu Yet al. (2010) The ERAD inhibitor Eeyarestatin I is a bifunctional compound with a membrane-binding domain and a p97/VCP inhibitory group. PLoS One 12: e15479.
Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, et al. (2006) Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 107: 4907�4916.
Mancini R, Fagioli C, Fra AM, Maggioni C, Sitia R (2000) Degradation of unassembled soluble Ig subunits by cytosolic proteasomes: evidence that retrotranslocation and degradation are coupled events. FASEB J 14: 769-778.
Werner ED, Brodsky JL, McCracken AA. Proteasome-dependent endoplasmic reticulum-associated protein degradation: an unconventional route to a familiar fate (1996) Proc Natl Acad Sci U S A 93: 13797-13801.
O'Hare T, Wiens GD, Whitcomb EA, Enns CA, Rittenberg MB (1999) Cutting edge: proteasome involvement in the degradation of unassembled Ig light chains.�J Immunol�163: 11-14.
Wacker SA, Houghtaling BR, Elemento O, Kapoor TM (2012) Using transcriptome sequencing to identify mechanisms of drug action and resistance. Nat Chem Biol 8: 235-237.
Stessman HA, Baughn LB, Sarver A, Xia T, Deshpande R, et al. (2013) Profiling bortezomib resistance identifies secondary therapies in a mouse myeloma model. Cancer Ther 12: 1140-1150.
Shuqing L�, Jianmin Wang (2013) The resistance mechanisms of proteasome inhibitor bortezomib. Biomarker Research 7771: 1-13.
Suzuki E, Demo S, Deu E, Keats J, Arastu-Kapur S, et al. (2011) Molecular mechanisms of bortezomib resistant adenocarcinoma cells. PLoS One 6: e27996.
Franke NE, Niewerth D, Assaraf YG, van Meerloo J, Vojtekova K, et al. (2012) Impaired bortezomib binding to mutant �5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells. Leukemia 26: 757-768.
Leung-Hagesteijn C, Erdmann N, Cheung G, Keats JJ, Stewart AK, et al. (2013) Xbp1s-negative tumor B cells and pre-plasmablasts mediate therapeutic proteasome inhibitor resistance in multiple myeloma. Cancer Cell 24: 289-304.
Mujtaba T, Dou QP (2011) Advances in the understanding of mechanisms and therapeutic use of bortezomib. Discov Med 12: 471-480.
Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, et al. (2002) Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 99: 14374-14379.
Davenport EL, Moore HE, Dunlop AS, Sharp SY, Workman P, et al. (2007) Heat shock protein inhibition is associated with activation of the unfolded protein response pathway in myeloma plasma cells. Blood 110: 2641-2649.
Zong WX, Li C, Hatzivassiliou G, Lindsten T, Yu QC, et al. (2003) Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis.�J Cell Biol 162: 59�69.
Selimovic D, Porzig BB, El-Khattouti A, Badura HE, Ahmad M, et al. (2013) Bortezomib/proteasome inhibitor triggers both apoptosis and autophagy-dependent pathways in melanoma cells. Cell Signal 25: 308-318.
Yu C, Rahmani M, Dent P, Grant S (2004) The hierarchical relationship between MAPK signaling and ROS generation in human leukemia cells undergoing apoptosis in response to the proteasome inhibitor Bortezomib. Exp Cell Res 295: 555-566.
Landowski TH, Megli CJ, Nullmeyer KD, Lynch RM, Dorr RT (2005) Mitochondrial-mediated disregulation of Ca2+ is a critical determinant of Velcade (PS-341/bortezomib) cytotoxicity in myeloma cell lines.�Cancer Res 65: 3828�3836.
Hemeryck A, Geerts R, Monbaliu J, Hassler S, Verhaeghe T, et al. (2007) Tissue distribution and depletion kinetics of bortezomib and bortezomib-related radioactivity in male rats after single and repeated intravenous injection of 14 C-bortezomib. Cancer Chemother Pharmacol 60: 777-787.
Mulligan G, Mitsiades C, Bryant B, Zhan F, Chng WJ, et al. (2007) Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib. Blood 109: 3177-3188.
Khong T, Spencer A. Targeting HSP 90 induces apoptosis and inhibits critical survival and proliferation pathways in multiple myeloma (2011) Mol Cancer Ther 10:1909-1917.
Rou� G, P�rez-Gal�n P, Mozos A, L�pez-Guerra M, Xargay-Torrent S, et al. (2011) 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. Blood 117: 1270-1279.
Auner HW, Moody AM, Ward TH, Kraus M, Milan E, et al. (2013) Combined Inhibition of p97 and the Proteasome Causes Lethal Disruption of the Secretory Apparatus in Multiple Myeloma Cells. PLoS One 8: e74415.





Reference link 
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=In+vivo+stim1.%09Alkalay+I%2C+Yaron+A%2C+Hatzubai+A%2C+Jung+S%2C+Avraham+A.+In+vivo+stimulation+of+I+kappa+B+phosphorylation+is+not+sufficient+to+activate+NF-kappa+B.+Mol+Cell+Biol" http://www.ncbi.nlm.nih.gov/pubmed/?term=In+vivo+stim1.%09Alkalay+I%2C+Yaron+A%2C+Hatzubai+A%2C+Jung+S%2C+Avraham+A.+In+vivo+stimulation+of+I+kappa+B+phosphorylation+is+not+sufficient+to+activate+NF-kappa+B.+Mol+Cell+Biol
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=Stimulation-dependent+I+kappa+B+alpha+phosphorylation+marks+the+NF-kappa+B+inhibitor+for+degradation+via+the+ubiquitin-proteasome+pathway.+Proc+Natl+Acad+Sci+U+S+A.92%3A+10599-10603" http://www.ncbi.nlm.nih.gov/pubmed/?term=Stimulation-dependent+I+kappa+B+alpha+phosphorylation+marks+the+NF-kappa+B+inhibitor+for+degradation+via+the+ubiquitin-proteasome+pathway.+Proc+Natl+Acad+Sci+U+S+A.92%3A+10599-10603.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=3.%09Kanarek+N%2C+London+N%2C+Schueler-Furman+O%2C+Ben-Neriah+Y+(2010)+Ubiquitination+and+degradation+of+the+inhibitors+of+NF-kappaB.+Cold+Spring+Harb+Perspect+Biol+2(2)%3A+a000166" http://www.ncbi.nlm.nih.gov/pubmed/?term=3.%09Kanarek+N%2C+London+N%2C+Schueler-Furman+O%2C+Ben-Neriah+Y+(2010)+Ubiquitination+and+degradation+of+the+inhibitors+of+NF-kappaB.+Cold+Spring+Harb+Perspect+Biol+2(2)%3A+a000166.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=4.%09Mitsiades+N%2C+Mitsiades+CS%2C+Poulaki+V%2C+Chauhan+D%2C+Richardson+PG%2C+et+al.+(2002)+Biologic+sequelae+of+nuclear+factor-kappaB+blockade+in+multiple+myeloma%3A+therapeutic+applications.+Blood+99%3A+4079-4086" http://www.ncbi.nlm.nih.gov/pubmed/?term=4.%09Mitsiades+N%2C+Mitsiades+CS%2C+Poulaki+V%2C+Chauhan+D%2C+Richardson+PG%2C+et+al.+(2002)+Biologic+sequelae+of+nuclear+factor-kappaB+blockade+in+multiple+myeloma%3A+therapeutic+applications.+Blood+99%3A+4079-4086.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=5.%09Hideshima+T%2C+Chauhan+D%2C+Richardson+P%2C+Mitsiades+C%2C+Mitsiades+N%2C+et+al.+(2002)+NF-kappa+B+as+a+therapeutic+target+in+multiple+myeloma.+J+Biol+Chem+277%3A+16639-16647" http://www.ncbi.nlm.nih.gov/pubmed/?term=5.%09Hideshima+T%2C+Chauhan+D%2C+Richardson+P%2C+Mitsiades+C%2C+Mitsiades+N%2C+et+al.+(2002)+NF-kappa+B+as+a+therapeutic+target+in+multiple+myeloma.+J+Biol+Chem+277%3A+16639-16647.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=6.%09Fern%C3%A1ndez+Y%2C+Verhaegen+M%2C+Miller+TP%2C+Rush+JL%2C+Steiner+P%2C+et+al.+(2005)+Differential+regulation+of+noxa+in+normal+melanocytes+and+melanoma+cells+by+proteasome+inhibition%3A+therapeutic+implications.+Cancer+Res+65%3A+6294-6304" http://www.ncbi.nlm.nih.gov/pubmed/?term=6.%09Fern%C3%A1ndez+Y%2C+Verhaegen+M%2C+Miller+TP%2C+Rush+JL%2C+Steiner+P%2C+et+al.+(2005)+Differential+regulation+of+noxa+in+normal+melanocytes+and+melanoma+cells+by+proteasome+inhibition%3A+therapeutic+implications.+Cancer+Res+65%3A+6294-6304.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=7.%09Befani+CD%2C+Vlachostergios+PJ%2C+Hatzidaki+E%2C+Patrikidou+A%2C+Bonanou+S%2C+et+al.+(2012)+Bortezomib+represses+HIF-1%CE%B1+protein+expression+and+nuclear+accumulation+by+inhibiting+both+PI3K%2FAkt%2FTOR+and+MAPK+pathways+in+prostate+cancer+cells.+J+Mol+Med+(Berl)+90%3A+45-54" http://www.ncbi.nlm.nih.gov/pubmed/?term=7.%09Befani+CD%2C+Vlachostergios+PJ%2C+Hatzidaki+E%2C+Patrikidou+A%2C+Bonanou+S%2C+et+al.+(2012)+Bortezomib+represses+HIF-1%CE%B1+protein+expression+and+nuclear+accumulation+by+inhibiting+both+PI3K%2FAkt%2FTOR+and+MAPK+pathways+in+prostate+cancer+cells.+J+Mol+Med+(Berl)+90%3A+45-54.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=8.%09Nawrocki+ST%2C+Carew+JS%2C+Pino+MS%2C+Highshaw+RA%2C+Dunner+K+Jr%2C+et+al.+(2005)+Bortezomib+sensitizes+pancreatic+cancer+cells+to+endoplasmic+reticulum+stress-mediated+apoptosis.+Cancer+Res+65%3A+11658%E2%80%9311666" http://www.ncbi.nlm.nih.gov/pubmed/?term=8.%09Nawrocki+ST%2C+Carew+JS%2C+Pino+MS%2C+Highshaw+RA%2C+Dunner+K+Jr%2C+et+al.+(2005)+Bortezomib+sensitizes+pancreatic+cancer+cells+to+endoplasmic+reticulum+stress-mediated+apoptosis.+Cancer+Res+65%3A+11658%E2%80%9311666.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=9.%09Nawrocki+ST%2C+Carew+JS%2C+Dunner+K+Jr%2C+Boise+LH%2C+Chiao+PJ%2C+et+al.+(2005)+Bortezomib+inhibits+PKR-like+endoplasmic+reticulum+(ER)+kinase+and+induces+apoptosis+via+ER+stress+in+human+pancreatic+cancer+cells.+Cancer+Res+65%3A+11510%E2%80%9311519" http://www.ncbi.nlm.nih.gov/pubmed/?term=9.%09Nawrocki+ST%2C+Carew+JS%2C+Dunner+K+Jr%2C+Boise+LH%2C+Chiao+PJ%2C+et+al.+(2005)+Bortezomib+inhibits+PKR-like+endoplasmic+reticulum+(ER)+kinase+and+induces+apoptosis+via+ER+stress+in+human+pancreatic+cancer+cells.+Cancer+Res+65%3A+11510%E2%80%9311519.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=10.%09Yoshida+H%2C+Matsui+T%2C+Yamamoto+A%2C+Okada+T%2C+Mori+K+(2001)+XBP1+mRNA+is+induced+by+ATF6+and+spliced+by+IRE1+in+response+to+ER+stress+to+produce+a+highly+active+transcription+factor.+Cell+107%3A+881-891" http://www.ncbi.nlm.nih.gov/pubmed/?term=10.%09Yoshida+H%2C+Matsui+T%2C+Yamamoto+A%2C+Okada+T%2C+Mori+K+(2001)+XBP1+mRNA+is+induced+by+ATF6+and+spliced+by+IRE1+in+response+to+ER+stress+to+produce+a+highly+active+transcription+factor.+Cell+107%3A+881-891.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=11.%09Lee+AH%2C+Iwakoshi+NN%2C+Glimcher+LH.+XBP-1+regulates+a+subset+of+endoplasmic+reticulum+resident+chaperone+genes+in+the+unfolded+protein+response+(2003).+Mol+Cell+Biol+23%3A+7448-7459" http://www.ncbi.nlm.nih.gov/pubmed/?term=11.%09Lee+AH%2C+Iwakoshi+NN%2C+Glimcher+LH.+XBP-1+regulates+a+subset+of+endoplasmic+reticulum+resident+chaperone+genes+in+the+unfolded+protein+response+(2003).+Mol+Cell+Biol+23%3A+7448-7459.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/12846805" http://www.ncbi.nlm.nih.gov/pubmed/12846805
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=13.%09Reimold+AM%2C+Iwakoshi+NN%2C+Manis+J%2C+Vallabhajosyula+P%2C+Szomolanyi-Tsuda+E%2C+et+al.+Plasma+cell+differentiation+requires+the+transcription+factor+XBP-1+(2001)+Nature+412%3A+300-307" http://www.ncbi.nlm.nih.gov/pubmed/?term=13.%09Reimold+AM%2C+Iwakoshi+NN%2C+Manis+J%2C+Vallabhajosyula+P%2C+Szomolanyi-Tsuda+E%2C+et+al.+Plasma+cell+differentiation+requires+the+transcription+factor+XBP-1+(2001)+Nature+412%3A+300-307.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=14.%09Iwakoshi+NN%2C+Lee+AH%2C+Vallabhajosyula+P%2C+Otipoby+KL%2C+Rajewsky+K%2C+et+al.+(2003)+Plasma+cell+differentiation+and+the+unfolded+protein+response+intersect+at+the+transcription+factor+XBP-1.+Nat+Immunol+4%3A+321-329" http://www.ncbi.nlm.nih.gov/pubmed/?term=14.%09Iwakoshi+NN%2C+Lee+AH%2C+Vallabhajosyula+P%2C+Otipoby+KL%2C+Rajewsky+K%2C+et+al.+(2003)+Plasma+cell+differentiation+and+the+unfolded+protein+response+intersect+at+the+transcription+factor+XBP-1.+Nat+Immunol+4%3A+321-329.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=15.%09Gass+JN%2C+Gifford+NM%2C+Brewer+JW+(2002)+Activation+of+an+unfolded+protein+response+during+differentiation+of+antibody-secreting+B+cells.+J+Biol+Chem+277%3A+49047%E2%80%9349054" http://www.ncbi.nlm.nih.gov/pubmed/?term=15.%09Gass+JN%2C+Gifford+NM%2C+Brewer+JW+(2002)+Activation+of+an+unfolded+protein+response+during+differentiation+of+antibody-secreting+B+cells.+J+Biol+Chem+277%3A+49047%E2%80%9349054.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=16.%09Kim+R%2C+Emi+M%2C+Tanabe+K%2C+Murakami+S+(2006)+Role+of+the+unfolded+protein+response+in+cell+death.+Apoptosis+11%3A+5%E2%80%9313" http://www.ncbi.nlm.nih.gov/pubmed/?term=16.%09Kim+R%2C+Emi+M%2C+Tanabe+K%2C+Murakami+S+(2006)+Role+of+the+unfolded+protein+response+in+cell+death.+Apoptosis+11%3A+5%E2%80%9313.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=17.%09Sano+R%2C+Reed+JC.+ER+stress-induced+cell+death+mechanisms+(2013)+Biochim+Biophys+Acta+1833%3A+3460-3470" http://www.ncbi.nlm.nih.gov/pubmed/?term=17.%09Sano+R%2C+Reed+JC.+ER+stress-induced+cell+death+mechanisms+(2013)+Biochim+Biophys+Acta+1833%3A+3460-3470.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=18.%09McCullough+KD%2C+Martindale+JL%2C+Klotz+LO%2C+Aw+TY%2C+Holbrook+NJ+(2001)+Gadd153+sensitizes+cells+to+endoplasmic+reticulum+stress+by+down-regulating+Bcl2+and+perturbing+the+cellular+redox+state.+Mol+Cell+Biol+21%3A+1249-1259" http://www.ncbi.nlm.nih.gov/pubmed/?term=18.%09McCullough+KD%2C+Martindale+JL%2C+Klotz+LO%2C+Aw+TY%2C+Holbrook+NJ+(2001)+Gadd153+sensitizes+cells+to+endoplasmic+reticulum+stress+by+down-regulating+Bcl2+and+perturbing+the+cellular+redox+state.+Mol+Cell+Biol+21%3A+1249-1259.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=19.%09Harding+HP%2C+Zhang+Y%2C+Bertolotti+A%2C+Zeng+H%2C+Ron+D+(2000)+Perk+is+essential+for+translational+regulation+and+cell+survival+during+the+unfolded+protein+response.+Mol+Cell+5%3A+897-904" http://www.ncbi.nlm.nih.gov/pubmed/?term=19.%09Harding+HP%2C+Zhang+Y%2C+Bertolotti+A%2C+Zeng+H%2C+Ron+D+(2000)+Perk+is+essential+for+translational+regulation+and+cell+survival+during+the+unfolded+protein+response.+Mol+Cell+5%3A+897-904.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=20.%09Fribley+A%2C+Zeng+Q%2C+Wang+CY+(2004)+Proteasome+inhibitor+PS-341+induces+apoptosis+through+induction+of+endoplasmic+reticulum+stress-reactive+oxygen+species+in+head+and+neck+squamous+cell+carcinoma+cells.+Mol+Cell+Biol+24%3A+9695%E2%80%939704" http://www.ncbi.nlm.nih.gov/pubmed/?term=20.%09Fribley+A%2C+Zeng+Q%2C+Wang+CY+(2004)+Proteasome+inhibitor+PS-341+induces+apoptosis+through+induction+of+endoplasmic+reticulum+stress-reactive+oxygen+species+in+head+and+neck+squamous+cell+carcinoma+cells.+Mol+Cell+Biol+24%3A+9695%E2%80%939704.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=21.%09Meister+S%2C+Schubert+U%2C+Neubert+K%2C+Herrmann+K%2C+Burger+R%2C+et+al.+(2007)+Extensive+immunoglobulin+production+sensitizes+myeloma+cells+for+proteasome+inhibition.+Cancer+Res+67%3A+1783-1792" http://www.ncbi.nlm.nih.gov/pubmed/?term=21.%09Meister+S%2C+Schubert+U%2C+Neubert+K%2C+Herrmann+K%2C+Burger+R%2C+et+al.+(2007)+Extensive+immunoglobulin+production+sensitizes+myeloma+cells+for+proteasome+inhibition.+Cancer+Res+67%3A+1783-1792.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=22.%09Ri+M%2C+Iida+S%2C+Nakashima+T%2C+Miyazaki+H%2C+Mori+F%2C+et+al.+(2010)+Bortezomib-resistant+myeloma+cell+lines%3A+a+role+for+mutated+PSMB5+in+preventing+the+accumulation+of+unfolded+proteins+and+fatal+ER+stress.+Leukemia+24%3A+1506-1512" http://www.ncbi.nlm.nih.gov/pubmed/?term=22.%09Ri+M%2C+Iida+S%2C+Nakashima+T%2C+Miyazaki+H%2C+Mori+F%2C+et+al.+(2010)+Bortezomib-resistant+myeloma+cell+lines%3A+a+role+for+mutated+PSMB5+in+preventing+the+accumulation+of+unfolded+proteins+and+fatal+ER+stress.+Leukemia+24%3A+1506-1512.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=23.%09Cohen+Y%2C+Garach-Jehoshua+O%2C+Bar-Chaim+A%2C+Kornberg+A+(2012)+Niche-modulated+and+niche-modulating+genes+in+bone+marrow+cells.+Blood+Cancer+J+14%3A+2%3Ae97" http://www.ncbi.nlm.nih.gov/pubmed/?term=23.%09Cohen+Y%2C+Garach-Jehoshua+O%2C+Bar-Chaim+A%2C+Kornberg+A+(2012)+Niche-modulated+and+niche-modulating+genes+in+bone+marrow+cells.+Blood+Cancer+J+14%3A+2%3Ae97.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=24.%09Cohen+Y%2C+Gutwein+O%2C+Garach-Jehoshua+O%2C+Bar-Haim+A%2C+Kornberg+A+(2013)+The+proliferation+arrest+of+primary+tumor+cells+out-of-niche+is+associated+with+widespread+downregulation+of+mitotic+and+transcriptional+genes" http://www.ncbi.nlm.nih.gov/pubmed/?term=24.%09Cohen+Y%2C+Gutwein+O%2C+Garach-Jehoshua+O%2C+Bar-Haim+A%2C+Kornberg+A+(2013)+The+proliferation+arrest+of+primary+tumor+cells+out-of-niche+is+associated+with+widespread+downregulation+of+mitotic+and+transcriptional+genes.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=25.%09Wang+Q%2C+Shinkre+BA%2C+Lee+JG%2C+Weniger+MA%2C+Liu+Yet+al.+(2010)+The+ERAD+inhibitor+Eeyarestatin+I+is+a+bifunctional+compound+with+a+membrane-binding+domain+and+a+p97%2FVCP+inhibitory+group.+PLoS+One+12%3A+e15479" http://www.ncbi.nlm.nih.gov/pubmed/?term=25.%09Wang+Q%2C+Shinkre+BA%2C+Lee+JG%2C+Weniger+MA%2C+Liu+Yet+al.+(2010)+The+ERAD+inhibitor+Eeyarestatin+I+is+a+bifunctional+compound+with+a+membrane-binding+domain+and+a+p97%2FVCP+inhibitory+group.+PLoS+One+12%3A+e15479.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=26.%09Obeng+EA%2C+Carlson+LM%2C+Gutman+DM%2C+Harrington+WJ+Jr%2C+Lee+KP%2C+et+al.+(2006)+Proteasome+inhibitors+induce+a+terminal+unfolded+protein+response+in+multiple+myeloma+cells.+Blood+107%3A+4907%E2%80%934916" http://www.ncbi.nlm.nih.gov/pubmed/?term=26.%09Obeng+EA%2C+Carlson+LM%2C+Gutman+DM%2C+Harrington+WJ+Jr%2C+Lee+KP%2C+et+al.+(2006)+Proteasome+inhibitors+induce+a+terminal+unfolded+protein+response+in+multiple+myeloma+cells.+Blood+107%3A+4907%E2%80%934916.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=27.%09Mancini+R%2C+Fagioli+C%2C+Fra+AM%2C+Maggioni+C%2C+Sitia+R+(2000)+Degradation+of+unassembled+soluble+Ig+subunits+by+cytosolic+proteasomes%3A+evidence+that+retrotranslocation+and+degradation+are+coupled+events.+FASEB+J+14%3A+769-778" http://www.ncbi.nlm.nih.gov/pubmed/?term=27.%09Mancini+R%2C+Fagioli+C%2C+Fra+AM%2C+Maggioni+C%2C+Sitia+R+(2000)+Degradation+of+unassembled+soluble+Ig+subunits+by+cytosolic+proteasomes%3A+evidence+that+retrotranslocation+and+degradation+are+coupled+events.+FASEB+J+14%3A+769-778.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=28.%09Werner+ED%2C+Brodsky+JL%2C+McCracken+AA.+Proteasome-dependent+endoplasmic+reticulum-associated+protein+degradation%3A+an+unconventional+route+to+a+familiar+fate+(1996(+Proc+Natl+Acad+Sci+U+S+A+93%3A+13797-13801" http://www.ncbi.nlm.nih.gov/pubmed/?term=28.%09Werner+ED%2C+Brodsky+JL%2C+McCracken+AA.+Proteasome-dependent+endoplasmic+reticulum-associated+protein+degradation%3A+an+unconventional+route+to+a+familiar+fate+(1996(+Proc+Natl+Acad+Sci+U+S+A+93%3A+13797-13801.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=29.%09O%27Hare+T%2C+Wiens+GD%2C+Whitcomb+EA%2C+Enns+CA%2C+Rittenberg+MB+(1999)+Cutting+edge%3A+proteasome+involvement+in+the+degradation+of+unassembled+Ig+light+chains.+J+Immunol+163%3A+11-14" http://www.ncbi.nlm.nih.gov/pubmed/?term=29.%09O%27Hare+T%2C+Wiens+GD%2C+Whitcomb+EA%2C+Enns+CA%2C+Rittenberg+MB+(1999)+Cutting+edge%3A+proteasome+involvement+in+the+degradation+of+unassembled+Ig+light+chains.+J+Immunol+163%3A+11-14.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=30.%09Wacker+SA%2C+Houghtaling+BR%2C+Elemento+O%2C+Kapoor+TM+(2012)+Using+transcriptome+sequencing+to+identify+mechanisms+of+drug+action+and+resistance.+Nat+Chem+Biol+8%3A+235-237" http://www.ncbi.nlm.nih.gov/pubmed/?term=30.%09Wacker+SA%2C+Houghtaling+BR%2C+Elemento+O%2C+Kapoor+TM+(2012)+Using+transcriptome+sequencing+to+identify+mechanisms+of+drug+action+and+resistance.+Nat+Chem+Biol+8%3A+235-237.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=31.%09Stessman+HA%2C+Baughn+LB%2C+Sarver+A%2C+Xia+T%2C+Deshpande+R%2C+et+al.+(2013)+Profiling+bortezomib+resistance+identifies+secondary+therapies+in+a+mouse+myeloma+model.+Cancer+Ther+12%3A+1140-1150" http://www.ncbi.nlm.nih.gov/pubmed/?term=31.%09Stessman+HA%2C+Baughn+LB%2C+Sarver+A%2C+Xia+T%2C+Deshpande+R%2C+et+al.+(2013)+Profiling+bortezomib+resistance+identifies+secondary+therapies+in+a+mouse+myeloma+model.+Cancer+Ther+12%3A+1140-1150.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=32.%09Shuqing+L%C3%BC%2C+Jianmin+Wang+(2013)+The+resistance+mechanisms+of+proteasome+inhibitor+bortezomib.+Biomarker+Research+7771%3A+1-13" http://www.ncbi.nlm.nih.gov/pubmed/?term=32.%09Shuqing+L%C3%BC%2C+Jianmin+Wang+(2013)+The+resistance+mechanisms+of+proteasome+inhibitor+bortezomib.+Biomarker+Research+7771%3A+1-13.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=33.%09Suzuki+E%2C+Demo+S%2C+Deu+E%2C+Keats+J%2C+Arastu-Kapur+S%2C+et+al.+(2011)+Molecular+mechanisms+of+bortezomib+resistant+adenocarcinoma+cells.+PLoS+One+6%3A+e27996" http://www.ncbi.nlm.nih.gov/pubmed/?term=33.%09Suzuki+E%2C+Demo+S%2C+Deu+E%2C+Keats+J%2C+Arastu-Kapur+S%2C+et+al.+(2011)+Molecular+mechanisms+of+bortezomib+resistant+adenocarcinoma+cells.+PLoS+One+6%3A+e27996.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=34.%09Franke+NE%2C+Niewerth+D%2C+Assaraf+YG%2C+van+Meerloo+J%2C+Vojtekova+K%2C+et+al.+(2012)+Impaired+bortezomib+binding+to+mutant+%CE%B25+subunit+of+the+proteasome+is+the+underlying+basis+for+bortezomib+resistance+in+leukemia+cells.+Leukemia+26%3A+757-768" http://www.ncbi.nlm.nih.gov/pubmed/?term=34.%09Franke+NE%2C+Niewerth+D%2C+Assaraf+YG%2C+van+Meerloo+J%2C+Vojtekova+K%2C+et+al.+(2012)+Impaired+bortezomib+binding+to+mutant+%CE%B25+subunit+of+the+proteasome+is+the+underlying+basis+for+bortezomib+resistance+in+leukemia+cells.+Leukemia+26%3A+757-768.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=Leung-Hagesteijn+C%2C+Erdmann+N%2C+Cheung+G%2C+Keats+JJ%2C+Stewart+AK%2C+et+al.+(2013)+Xbp1s-negative+tumor+B+cells+and+pre-plasmablasts+mediate+therapeutic+proteasome+inhibitor+resistance+in+multiple+myeloma.+Cancer+Cell+24%3A+289-304" http://www.ncbi.nlm.nih.gov/pubmed/?term=Leung-Hagesteijn+C%2C+Erdmann+N%2C+Cheung+G%2C+Keats+JJ%2C+Stewart+AK%2C+et+al.+(2013)+Xbp1s-negative+tumor+B+cells+and+pre-plasmablasts+mediate+therapeutic+proteasome+inhibitor+resistance+in+multiple+myeloma.+Cancer+Cell+24%3A+289-304.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=36.%09Mujtaba+T%2C+Dou+QP+(2011)+Advances+in+the+understanding+of+mechanisms+and+therapeutic+use+of+bortezomib.+Discov+Med+12%3A+471-480" http://www.ncbi.nlm.nih.gov/pubmed/?term=36.%09Mujtaba+T%2C+Dou+QP+(2011)+Advances+in+the+understanding+of+mechanisms+and+therapeutic+use+of+bortezomib.+Discov+Med+12%3A+471-480.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=37.%09Mitsiades+N%2C+Mitsiades+CS%2C+Poulaki+V%2C+Chauhan+D%2C+Fanourakis+G%2C+et+al.+(2002)+Molecular+sequelae+of+proteasome+inhibition+in+human+multiple+myeloma+cells.+Proc+Natl+Acad+Sci+U+S+A+99%3A+14374-14379" http://www.ncbi.nlm.nih.gov/pubmed/?term=37.%09Mitsiades+N%2C+Mitsiades+CS%2C+Poulaki+V%2C+Chauhan+D%2C+Fanourakis+G%2C+et+al.+(2002)+Molecular+sequelae+of+proteasome+inhibition+in+human+multiple+myeloma+cells.+Proc+Natl+Acad+Sci+U+S+A+99%3A+14374-14379.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=38.%09Davenport+EL%2C+Moore+HE%2C+Dunlop+AS%2C+Sharp+SY%2C+Workman+P%2C+et+al.+(2007)+Heat+shock+protein+inhibition+is+associated+with+activation+of+the+unfolded+protein+response+pathway+in+myeloma+plasma+cells.+Blood+110%3A+2641-2649" http://www.ncbi.nlm.nih.gov/pubmed/?term=38.%09Davenport+EL%2C+Moore+HE%2C+Dunlop+AS%2C+Sharp+SY%2C+Workman+P%2C+et+al.+(2007)+Heat+shock+protein+inhibition+is+associated+with+activation+of+the+unfolded+protein+response+pathway+in+myeloma+plasma+cells.+Blood+110%3A+2641-2649.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=Zong+WX%2C+Li+C%2C+Hatzivassiliou+G%2C+Lindsten+T%2C+Yu+QC" http://www.ncbi.nlm.nih.gov/pubmed/?term=Zong+WX%2C+Li+C%2C+Hatzivassiliou+G%2C+Lindsten+T%2C+Yu+QC
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=40.%09Selimovic+D%2C+Porzig+BB%2C+El-Khattouti+A%2C+Badura+HE%2C+Ahmad+M%2C+et+al.+(2013)+Bortezomib%2Fproteasome+inhibitor+triggers+both+apoptosis+and+autophagy-dependent+pathways+in+melanoma+cells.+Cell+Signal+25%3A+308-318" http://www.ncbi.nlm.nih.gov/pubmed/?term=40.%09Selimovic+D%2C+Porzig+BB%2C+El-Khattouti+A%2C+Badura+HE%2C+Ahmad+M%2C+et+al.+(2013)+Bortezomib%2Fproteasome+inhibitor+triggers+both+apoptosis+and+autophagy-dependent+pathways+in+melanoma+cells.+Cell+Signal+25%3A+308-318.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=Yu+C%2C+Rahmani+M%2C+Dent+P%2C+Grant+S+(2004)+The+hierarchical+relationship+between+MAPK+signaling+and+ROS+generation+in+human+leukemia+cells+undergoing+apoptosis+in+response+to+the+proteasome+inhibitor+Bortezomib.+Exp+Cell+Res+295%3A+555-566" http://www.ncbi.nlm.nih.gov/pubmed/?term=Yu+C%2C+Rahmani+M%2C+Dent+P%2C+Grant+S+(2004)+The+hierarchical+relationship+between+MAPK+signaling+and+ROS+generation+in+human+leukemia+cells+undergoing+apoptosis+in+response+to+the+proteasome+inhibitor+Bortezomib.+Exp+Cell+Res+295%3A+555-566.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=42.%09Landowski+TH%2C+Megli+CJ%2C+Nullmeyer+KD%2C+Lynch+RM%2C+Dorr+RT+(2005)+Mitochondrial-mediated+disregulation+of+Ca2%2B+is+a+critical+determinant+of+Velcade+(PS-341%2Fbortezomib)+cytotoxicity+in+myeloma+cell+lines.+Cancer+Res+65%3A+3828%E2%80%933836" http://www.ncbi.nlm.nih.gov/pubmed/?term=42.%09Landowski+TH%2C+Megli+CJ%2C+Nullmeyer+KD%2C+Lynch+RM%2C+Dorr+RT+(2005)+Mitochondrial-mediated+disregulation+of+Ca2%2B+is+a+critical+determinant+of+Velcade+(PS-341%2Fbortezomib)+cytotoxicity+in+myeloma+cell+lines.+Cancer+Res+65%3A+3828%E2%80%933836.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=Hemeryck+A%2C+Geerts+R%2C+Monbaliu+J%2C+Hassler+S%2C+Verhaeghe+T%2C+et+al.+(2007)+Tissue+distribution+and+depletion+kinetics+of+bortezomib+and+bortezomib-related+radioactivity+in+male+rats+after+single+and+repeated+intravenous+injection+of+14+C-bortezomib.+Cancer+Chemother+Pharmacol+60%3A+777-787" http://www.ncbi.nlm.nih.gov/pubmed/?term=Hemeryck+A%2C+Geerts+R%2C+Monbaliu+J%2C+Hassler+S%2C+Verhaeghe+T%2C+et+al.+(2007)+Tissue+distribution+and+depletion+kinetics+of+bortezomib+and+bortezomib-related+radioactivity+in+male+rats+after+single+and+repeated+intravenous+injection+of+14+C-bortezomib.+Cancer+Chemother+Pharmacol+60%3A+777-787.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=44.%09Mulligan+G%2C+Mitsiades+C%2C+Bryant+B%2C+Zhan+F%2C+Chng+WJ%2C+et+al.+(2007)+Gene+expression+profiling+and+correlation+with+outcome+in+clinical+trials+of+the+proteasome+inhibitor+bortezomib.+Blood+109%3A+3177-3188" http://www.ncbi.nlm.nih.gov/pubmed/?term=44.%09Mulligan+G%2C+Mitsiades+C%2C+Bryant+B%2C+Zhan+F%2C+Chng+WJ%2C+et+al.+(2007)+Gene+expression+profiling+and+correlation+with+outcome+in+clinical+trials+of+the+proteasome+inhibitor+bortezomib.+Blood+109%3A+3177-3188.
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��&�'�(�)�*�6�\�^�_�������������������<�=�>�?�@�L�O�Q�R�U�V�W�X�Y�e����������������������ӯ����Ӛ�ӯ����Ӛ�ӯ����Ӛ�ӯ����Ӛ�ӯ����Ӛ�ӯ�����Ӛ�ӯU(h�G�h�G�CJOJQJ^JaJmH	sH	"h�G�CJOJQJ^JaJmH	sH	"h�Z~CJOJQJ^JaJmH	sH	+jh�G�CJOJQJU^JaJmH	sH	,h�,h�G�0JCJOJQJ^JaJmH	sH	<http://www.ncbi.nlm.nih.gov/pubmed/?term=45.%09Khong+T%2C+Spencer+A.+Targeting+HSP+90+induces+apoptosis+and+inhibits+critical+survival+and+proliferation+pathways+in+multiple+myeloma+(2011)+Mol+Cancer+Ther+10%3A1909-1917" http://www.ncbi.nlm.nih.gov/pubmed/?term=45.%09Khong+T%2C+Spencer+A.+Targeting+HSP+90+induces+apoptosis+and+inhibits+critical+survival+and+proliferation+pathways+in+multiple+myeloma+(2011)+Mol+Cancer+Ther+10%3A1909-1917.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=46.%09Rou%C3%A9+G%2C+P%C3%A9rez-Gal%C3%A1n+P%2C+Mozos+A%2C+L%C3%B3pez-Guerra+M%2C+Xargay-Torrent+S%2C+et+al.+(2011)+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%2FGrp78.+Blood+117%3A+1270-1279" http://www.ncbi.nlm.nih.gov/pubmed/?term=46.%09Rou%C3%A9+G%2C+P%C3%A9rez-Gal%C3%A1n+P%2C+Mozos+A%2C+L%C3%B3pez-Guerra+M%2C+Xargay-Torrent+S%2C+et+al.+(2011)+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%2FGrp78.+Blood+117%3A+1270-1279.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed/?term=47.%09Auner+HW%2C+Moody+AM%2C+Ward+TH%2C+Kraus+M%2C+Milan+E%2C+et+al.+(2013)+Combined+Inhibition+of+p97+and+the+Proteasome+Causes+Lethal+Disruption+of+the+Secretory+Apparatus+in+Multiple+Myeloma+Cells.+PLoS+One+8%3A+e74415" http://www.ncbi.nlm.nih.gov/pubmed/?term=47.%09Auner+HW%2C+Moody+AM%2C+Ward+TH%2C+Kraus+M%2C+Milan+E%2C+et+al.+(2013)+Combined+Inhibition+of+p97+and+the+Proteasome+Causes+Lethal+Disruption+of+the+Secretory+Apparatus+in+Multiple+Myeloma+Cells.+PLoS+One+8%3A+e74415.












Figure legends
Figure 1: Commonly modulated genes following in vitro exposure to bortezomib 
List of the genes which were commonly modulated in the BM samples from patients with either bortezomib responsive (cases A, B) or bortezomib resistant myeloma (cases C, D) following 6-8 hours incubation with the drug (2 �g/ml) as compared with the expression in the corresponding untreated BM samples. HSPs and related chaperone coding genes are marked in yellow. The unannotated genes are denoted by their Affimetrix ID number.

Figure 2: The genes induced in BM samples from MM patients after exposure to bortezomib as well as in cancer cells exposed to direct ERAD inhibitors
List of the genes which were induced in both the BM samples from our MM patients (cases A-D) after in vitro exposure to bortezomib (2 �g/ml) as well as i��%�'�(�������������������������������������#�7�A�D�H���ì�������ì��ٚ�m�m��XJ�XJh�E^CJOJQJ^JaJ(h�@^h�E^CJOJQJ^JaJmH	sH	(h�E^5�CJOJQJ\�^JaJmH	sH	.h�@^h�E^5�CJOJQJ\�^JaJmH	sH	"h�E^CJOJQJ^JaJmH	sH	,h�,h�G�0JCJOJQJ^JaJmH	sH	+jh�G�CJOJQJU^JaJmH	sH	"h�G�CJOJQJ^JaJmH	sH	(h�G�h�G�CJOJQJ^JaJmH	sH	��������������������������������������������������$a$d��dhgd�E^d�gd�E^d�gd�|8H�����������0����������V�j�������7S�����IJ����p�p��IJ��n�U1h�@^h�E^CJOJQJ^JaJfHq�
����U(h�E^5�CJOJQJ\�^JaJmH	sH	.h�@^h�E^5�CJOJQJ\�^JaJmH	sH	(h�E^CJOJQJZ�^JaJmH	o(sH	"h�E^CJOJQJ^JaJmH	sH	(h�4�h�E^CJOJQJ^JaJmH	sH	"h�E^CJOJQJ^JaJmH	sH	(h�@^h�E^CJOJQJ^JaJmH	sH	n cancer cells treated with the direct ERAD inhibitors 5-nitrofuryl-acrolein (5-NA)��or Eeyarestatin I (EerI) in the study by Wang et al. (see ref. #25).  









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