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A Highly Epothilone B–Resistant A549 Cell Line with Mutations in Tubulin That Confer Drug Dependence

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A Highly Epothilone B–Resistant A549 Cell Line with Mutations in Tubulin That Confer Drug Dependence 987 A highly epothilone B–resistant A549 cell line with mutations in tubulin that confer drug dependence Chia-Ping Huang Yang,1 Pascal Verdier-Pinard,1 could modulate the interactions between tubulin and Fang Wang,1 Eva Lippaine-Horvath,1 Lifeng He,1 regulatory proteins. We propose that the BVal60Phe Dansu Li,2 Gerhard Ho¨fle,3 Iwao Ojima,2 mutation plays a critical role in the drug-dependent George A. Orr,1 and Susan Band Horwitz1 phenotype of EpoB480 cells. [Mol Cancer Ther 2005; 4(6):987–95] 1Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York; 2Department of Chemistry, State University of New York at Stony Brook, Stony Brook, Introduction New York; and 3Department of Natural Product Chemistry, Geselleschaft fur Biotechnologische Forschung, The tubulin/microtubule system is a validated target for Braunschweig, Germany antitumordrugs.Onesuchdrug,Taxol,hasbeen approved by the Food and Drug Administration for the treatment of ovarian, breast, and non–small cell lung Abstract carcinomas. The drug has a specific binding site on the A 95-fold epothilone B (EpoB)–resistant, but not depen- microtubule (1, 2), and incubation of cells with Taxol dent, A549 human lung carcinoma cell line, A549.EpoB40 results in the formation of stable bundles of microtubules (EpoB40), has a Gln to Glu mutation at residue 292 that (3). Low concentrations of Taxol disrupt the normal B is situated near the M-loop of I-tubulin. Further selection polymerization/depolymerization cycle of microtubules of this cell line with higher concentrations of EpoB pro- and suppress microtubule dynamics (4). Treatment of f duced A549.EpoB480 (EpoB480), which is 900-fold cells with Taxol induces aberrant mitosis at low concen- resistant to EpoB. This cell line, like EpoB40, exhibits trations of drug and mitotic arrest at higher concentra- cross-resistance to Taxol and extreme sensitivity to vin- tions of drug (5). blastine, but in contrast to EpoB40 it is unusually depen- A new class of microtubule-stabilizing agents, the dent on EpoB, requiring a minimum of 125 nmol/L EpoB epothilones, has been identified (6). The epothilones were B to maintain normal growth. Sequence analysis of the - originally isolated from a Myxobacterium fermentation A tubulin and K 1-tubulin genes in EpoB480 showed that, broth (7) and are currently undergoing phase II clinical B B in addition to the 292 mutation, 60 was mutated from trials as anticancer agents (8, 9). Like Taxol, the drug A Val to Phe and 195 was mutated from Leu to Met. Mass induces tubulin polymerization in the absence of GTP and 60 spectrometry indicated that both the Val Phe and causes microtubule stabilization and bundling (6, 10). 195 B A Leu Met mutations in I- and K 1-tubulin, respectively, Although a common pharmacophore shared by taxanes were expressed at the protein level. Molecular modeling and epothilones was proposed (11, 12), recent electron B indicated that 60 is located at the end of the H1-S2 crystallography studies have shown that tubulin has an loop that has been implicated as a principal partner of the indiscriminate binding pocket into which Taxol and M-loop for contacts between protofilaments. A mutation epothilone A make unique contacts (13). Epothilone is B at 60 could inhibit the lateral contacts between proto- not a substrate for the multidrug transporter P-glycopro- A filaments, thereby destabilizing microtubules. 195 is tein, the MDR1 gene product, and is active in Taxol- located at the external surface of the microtubule that resistant cell lines and tumors that express P-glycoprotein has been proposed as the domain that interacts with a (6, 8). variety of endogenous proteins, such as stathmin and In addition to induction of P-glycoprotein, other potential A microtubule-associated protein 4. A mutation at 195 mechanisms of Taxol resistance, at the level of the microtubule, have been proposed. These include altered expression of h-tubulin isotypes, point mutations in tubulin leading to alterations in microtubule dynamics, and altered Received 1/19/05; revised 3/8/05; accepted 4/12/05. expression/posttranslational modifications of tubulin reg- Grant support: U.S. Public Health Service, National Cancer Institute, grants CA083185 and CA077263; National Foundation for Cancer Research ulatory proteins, such as stathmin and microtubule- (S.B. Horwitz); and Department of Defense grant W81XWH-04-1-0754 associated protein 4 (MAP4; ref. 14). The Taxol dependence (C-P.H. Yang). phenotype has also been described as cancer cells develop The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked resistance (15–18), although the mechanism underlying advertisement in accordance with 18 U.S.C. Section 1734 solely to Taxol dependence is not understood. indicate this fact. Sequence analysis of class hI-tubulin from an epothi- Requests for reprints: Susan B. Horwitz, Department of Molecular lone-resistant cell line, EpoB40, revealed a single point Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park h Avenue, Bronx, NY 10461. Phone: 718-430-2163; Fax: 718-430-8959. mutation at 292 (Gln to Glu) that is near the M-loop (19). E-mail: [email protected] This resistant cell line, derived from a human lung Copyright C 2005 American Association for Cancer Research. carcinoma A549 cell line by stepwise selection with EpoB, Mol Cancer Ther 2005;4(6). June 2005 Downloaded from mct.aacrjournals.org on September 24, 2021. © 2005 American Association for Cancer Research. 988 Tubulin Mutations and Taxol/Epothilone Dependence is maintained in 40 nmol/L EpoB and is 95-fold resistant lized pH gradient strips at pH 4.5 to 5.5 and run on an to EpoB and 22-fold cross-resistant to Taxol. Isoelectric IPGphor isoelectric focusing system. Immobilized pH focusing studies showed that the mutant hI-tubulin, but gradient strips were then fixed, stained with Coomassie not the wild type, was predominantly expressed in this blue, and destained as described (20). cell line (20). In the present study, further selection of Analysis of Protein BI- and KA1-Tubulin Mutations by EpoB40 cells with higher concentrations of EpoB resulted Mass Spectrometry in the cell line A549.EpoB480 (EpoB480), which is Tubulin was isolated from A549 and EpoB480 cells and maintained in 480 nmol/L EpoB and is highly dependent the masses of the tubulin isoforms were determined by on the drug for normal cell proliferation. It is proposed liquid chromatography-mass spectrometry analysis as that a critical mutation in hI-tubulin plays a role in Taxol/ described (21). EpoB dependence. Measurement of Polymerized Tubulin Soluble and polymerized tubulin were separated as described (22). Briefly, 5 Â 105 cells were suspended in Materials and Methods 150 AL hypotonic buffer (0.5% NP40, 0.1 mol/L MES, Materials and Cells 1 mmol/L EGTA, and 0.5 mmol/L MgCl2) and incubated at Epothilone B and Taxol were obtained as described (19). 37jC for 5 minutes in the presence or absence of 10 Amol/L 3 21-[ H]21-OH-EpoB was prepared by the reduction of 20- EpoB. Polymerized tubulin was collected by centrifugation 3 formyl-EpoB with NaB[ H]4. 20-Formyl-EpoB was derived at 16,000 Â g for 10 minutes at room temperature. The from EpoB in three steps via N-oxidation with m- pellet was solubilized in 200 AL SDS-PAGE sample buffer. chloroperbenzoic acid (forming N-oxide), rearrangement Fifty microliters of 4Â sample buffer were added to the with acetic anhydride ammonia in methanol (giving 21- supernatant that contained soluble tubulin. Proteins from 3 OH-EpoB), and Swern oxidation. [ H]Taxol was obtained both fractions were separated by SDS-PAGE, transferred to from the National Cancer Institute (Bethesda, MD). nitrocellulose, and immunoblotted using monoclonal anti– Monoclonal anti–a-tubulin antibody was purchased from a-tubulin antibody. The levels of tubulin in both fractions Sigma (St. Louis, MO) and polyclonal antistathmin anti- were quantitated by image analysis using Molecular body was from Calbiochem (La Jolla, CA). Anti-MAP4 Dynamics ImageQuant Software Version 3.3. antibody was kindly provided by Dr. Jeannette C. Bulinski Stathmin and MAP4 Protein Analysis (Columbia University, New York, NY). A549, a human For determination of stathmin levels, cell lysates were non–small cell lung cancer line, was grown in RPMI 1640 prepared as described (18). The samples were subjected to containing 10% fetal bovine serum. EpoB480 was devel- 15% SDS-PAGE, followed by Western blot analysis using a oped by stepwise selection of a 95-fold EpoB-resistant cell polyclonal antistathmin antibody. For MAP4 analysis, cells line EpoB40 (19) and was maintained in 480 nmol/L EpoB. were lysed in a buffer containing 10 mmol/L Tris-HCl CytotoxicityAssay (pH 7.5) and 1% SDS. The samples were boiled and A methylene blue–based cytotoxicity assay was done as analyzed by 5% urea-PAGE. Western blot analysis was previously described (19) to determine drug resistance done using a polyclonal antibody to MAP4. profiles of EpoB480. Modeling of theTubulin Mutation 3 3 [ H]Taxol and [ H]21-OH-EpoBAccumulation Studies Molecular modeling studies were done using the Deep- 5 Cells (5 Â 10 ) were plated in 35-mm culture dishes and View/Swiss-pdbViewer v3.7 software. The structure of a- maintained in drug-free medium for 3 to 4 hours. The and h-tubulin that interact with one molecule of epothilone medium was removed and fresh medium containing A was taken from Nettles et al. (13). 5 Amol/L [3H]Taxol (specific activity: 40 mCi/mmol) or 5 Amol/L [3H]21-OH-EpoB (specific activity: 10 mCi/ mmol) was added. Following incubation at 37jC for 1 Results hour, the cells were washed with PBS and lysed in 1 N EpoB480CellsAreUnusuallyDependentonEpoBfor NaOH at room temperature for 16 hours.
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