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Proteomic Identification of Aldo-Keto Reductase AKR1B10 Induction After Treatment of Colorectal Cancer Cells with the Proteasome Inhibitor Bortezomib

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Proteomic Identification of Aldo-Keto Reductase AKR1B10 Induction After Treatment of Colorectal Cancer Cells with the Proteasome Inhibitor Bortezomib Published OnlineFirst June 30, 2009; DOI: 10.1158/1535-7163.MCT-08-0987 1995 Proteomic identification of aldo-keto reductase AKR1B10 induction after treatment of colorectal cancer cells with the proteasome inhibitor bortezomib Judith Loeffler-Ragg,1 Doris Mueller,2 study shows for the first time a bortezomib-induced up- Gabriele Gamerith,1 Thomas Auer,1 regulation of AKR1B10. Small interfering RNA–mediated Sergej Skvortsov,1 Bettina Sarg,3 Ira Skvortsova,4 inhibition of this enzyme with known intracellular detoxi- Klaus J. Schmitz,6 Hans-Jörg Martin,7 fication function sensitized HRT-18 cells to therapy with Jens Krugmann,5 Hakan Alakus,8 Edmund Maser,7 the proteasome inhibitor. To further characterize the rele- vance of AKR1B10 for colorectal tumors,immunohisto- Jürgen Menzel,2 Wolfgang Hilbe,1 Herbert Lindner,3 6 1 chemical expression was shown in 23.2% of 125 tumor Kurt W. Schmid, and Heinz Zwierzina specimens. These findings indicate that AKR1B10 might Departments of 1Internal Medicine, 2Medical Genetics, be a target for combination therapy with bortezomib. Molecular and Clinical Pharmacology, 3Clinical Biochemistry, [Mol Cancer Ther 2009;8(7):1995–2006] 4Radiotherapy-Radiooncology,and 5Pathology,Innsbruck Medical University,Innsbruck,Austria; 6Department of Pathology and Neuropathology,Essen University Hospital,Duisburg-Essen Introduction 7 University,Essen,Germany; Institute of Toxicology and Colorectal cancer is a leading cause of cancer death through- Pharmacology for Natural Scientists,University Medical School Schleswig-Holstein,Kiel,Germany; and 8Department of Visceral out the world (1). Although chemotherapy has improved and Vascular Surgery,Cologne University,Cologne,Germany the outcome of patients with metastatic disease, new thera- pies with novel mechanisms of action are warranted. Major molecular pathways involved in the pathogenesis of colo- Abstract rectal carcinoma such as β-catenin, Smad4, p53, and nuclear Targeting the ubiquitin-proteasome pathway with the pro- factor κB (NF-κB) downstream of Ras are regulated by the teasome inhibitor bortezomib has emerged as a promising ubiquitin-proteasome system providing a rationale for pro- approach for the treatment of several malignancies. The teasome inhibition (2). The 26S proteasome, a large multica- cellular and molecular effects of this agent on colorectal talytic protease complex, degrades several regulatory cancer cells are poorly characterized. This study investi- proteins and inhibitors after their ligation with the protein gated the antiproliferative effect of bortezomib on colorec- ubiquitin and mediates various cellular functions such as tal cancer cell lines (Caco-2 and HRT-18). In order to transcription, stress response, cell cycle regulation, apopto- define the proteins potentially involved in the mechanisms sis, ribosome biogenesis, cellular differentiation, DNA re- of action,proteome profiling was applied to detect the pair, and oncogenesis. Its involvement in malignancy and proteins altered by bortezomib. The in vitro efficacy of the finding that it regulates the key antiapoptotic transcrip- bortezomib as a single agent in colorectal cancer cell lines tion factor NF-κB has formed the basis for the exploration of was confirmed. Proteome profiling with two-dimensional proteasome inhibition as an antineoplastic strategy (3). PAGE followed by mass spectrometry revealed the up- Bortezomib (Velcade, formerly known as PS-341) is a nov- regulation of the major inducible isoform of heat shock el dipeptide boronic acid that reversibly inhibits the chymo- protein 70 (hsp72) and lactate dehydrogenase B in both tryptic activity of the proteasome (4). Preclinical studies cell lines,as well as the induction of aldo-keto reductase have shown that this compound decreases proliferation, in- family 1 member B10 (AKR1B10) in HRT-18 cells. Both duces G2-M arrest and apoptosis, enhances the activity of AKR1B10 and hsp72 exert cell-protective functions. This chemotherapy or radiation, and reverses chemoresistance in a variety of hematologic and solid malignancy models. Bortezomib is already approved for the treatment of pa- Received 10/16/08; revised 4/15/09; accepted 5/4/09; published OnlineFirst tients with relapsed or refractory multiple myeloma and 6/30/09. has shown activity in solid tumors (5). In colorectal cancer, Grant support: Austrian National Bank (project no. 11681), the German preclinical testing with bortezomib has shown synergy with Research Council (DFG-MA 1704/5-1), and the Hans and Blanca Moser-Stiftung (J. Loeffler-Ragg). irinotecan or ionizing radiation and resulted in significant – The costs of publication of this article were defrayed in part by the tumor regression in xenograft models (6 8). However, the payment of page charges. This article must therefore be hereby marked results of clinical efficacy are very limited and biomarkers advertisement in accordance with 18 U.S.C. Section 1734 solely to related to response or resistance are lacking (9). indicate this fact. Recently, proteomic technologies evolved as a useful Requests for reprints: Judith Loeffler-Ragg, Department of Internal Medicine I, – Anichstrasse 35, 6020 Innsbruck, Austria. Phone: 43-512-504-23255; strategy to track biological responses to therapy (10 12). Fax: 43-512-504-24209. E-mail: [email protected] With this method, hundreds to thousands of proteins are Copyright © 2009 American Association for Cancer Research. displayed at the same time and dynamic changes in re- doi:10.1158/1535-7163.MCT-08-0987 sponse to drug therapy can be detected. To define proteins Mol Cancer Ther 2009;8(7). July 2009 Downloaded from mct.aacrjournals.org on September 27, 2021. © 2009 American Association for Cancer Research. Published OnlineFirst June 30, 2009; DOI: 10.1158/1535-7163.MCT-08-0987 1996 Induction of AKR1B10 by Bortezomib that are up-regulated or down-regulated after therapy with the manufacturer (Annexin V FITC Apoptosis Detection bortezomib, we created proteome profiles of the colorectal Kit; BD PharMingen). Corresponding cell culture assays cancer cell lines, HRT-18 and Caco-2, using two-dimensional were prepared in a six-well plate format (150,000 cells/well). PAGE (13). The highly differentiated Caco-2 cell line (dou- Two-dimensional PAGE bling time, 80 hours) and the poorly differentiated HRT-18 HRT-18 and Caco-2 cells (5 × 106) were seeded in T75 cell line (doubling time, 20 hours) are characterized by high flasks and analyzed with two-dimensional PAGE 6, 12, 24, epidermal growth factor receptor expression and a mutation and 48 h after treatment with 0.03 μmol/L of bortezomib. status with mutant APC/mutant p53/wild-type KRAS/ Controls were taken at times 0 and 24h. For sample prep- wild-type BRAF for Caco-2 and mutant APC/mutant p53/ aration, cells were scraped, harvested, and lysed as previ- mutant KRAS/wild-type BRAF for HRT-18 (11, 14–16). Dif- ously described (11). ferential analysis before and after therapy revealed three For first-dimension isoelectric focusing, 100 μg of protein proteins specifically up-regulated. Our data suggest that per sample diluted to 450 μL with rehydration buffer proteome-based technologies can reveal proteins influ- (7 mol/L urea, 2 mol/L thiourea, 1% ASB-14, 0.5% IPG enced by proteasome inhibition and help to further eluci- buffer, and 60 mmol/L DTT) were loaded on immobilized date the complex mode of action. 24cm (pH 3 –10) NL gradient strips (Amersham Biosciences). Active rehydration (50 V) was carried out at 20°C for 12 h. Isoelectric focusing was done at 250 V for 30 min, 500 V for Materials and Methods 1 h, 2,000 V for 1 h, and finally,at 8,000 Vuntil 55,000 V/h were Cell Cultures reached in total. The colorectal cancer cell lines Caco-2 and HRT-18 were For the second dimension, samples were separated on purchased from American Type Culture Collection. Caco-2 12.5% polyacrylamide gels with the Ettan DALTtwelve Sys- was grown in MEM with Earle's salts (PAA Laboratories) tem following the standard procedures recommended by supplemented with 2 mmol/L of L-glutamine, 1.5 g/L of the manufacturer (Amersham Biosciences). After electro- sodium bicarbonate, 0.1 mmol/L of nonessential amino phoresis, gels were silver-stained, scanned with ImageScan- acids, 50 units/mL of penicillin, 50 μg/mL of streptomycin, ner, and analyzed with ImageMaster 2D Platinum software and 10% FCS (v/v; Sigma-Aldrich). HRT-18 cells were (Amersham Biosciences). To obtain a standard gel for each maintained in RPMI 1640 (PAA Laboratories) containing individual cell line, spot detection and matching were done 2 mmol/L of L-glutamine, 50 units/mL of penicillin, using gels from three runs. These standard gels were then 50 μg/mL of streptomycin, and 10% FCS (v/v). Cultures matched to yield information about differentially expressed were incubated in a 5% CO2-humidified atmosphere. proteins. We selected spots overexpressed or underex- Drug Sensitivity Assays pressed by more than 4-fold to exclude artifacts caused by Bortezomib resolved in 0.9% NaCl was obtained from the gel-to-gel variation observed with silver staining, and then institutional pharmacy. Drug sensitivity testing was done checked spots by eye in order to avoid possible software er- using WST-1 assay and direct cell count for Caco-2 and rors (13, 18). HRT-18 cells, at different times (24, 48, 72, and 96 h) and Protein analysis was done as previously published (11). doses (range, 0.01–0.1 μmol/L) of bortezomib. These con- Three protein digests were separated using capillary high- centrations are within those achieved clinically in the performance liquid chromatography connected online to plasma of patients treated with bortezomib (17). To screen an LCQ ion trap instrument (ThermoFinnigan) equipped for IC50 values, an indirect measure of cell viability and with a nanospray interface. Tandem mass spectra were proliferation was done by determination of the metabolic searched against a human database using SEQUEST (LCQ activity of cells with a colorimetric assay based on cleav- BioWorks; ThermoFinnigan).
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