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Altered Erbb Receptor Signaling and Gene Expression in Cisplatin-Resistant Ovarian Cancer

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Altered Erbb Receptor Signaling and Gene Expression in Cisplatin-Resistant Ovarian Cancer Research Article Altered ErbB Receptor Signaling and Gene Expression in Cisplatin-Resistant Ovarian Cancer Kenneth Macleod, Peter Mullen, Jane Sewell, Genevieve Rabiasz, Sandra Lawrie, Eric Miller, John F. Smyth and Simon P. Langdon Cancer Research UK Centre, University of Edinburgh, Edinburgh, United Kingdom Abstract The erbB receptor family consists of the EGFR (erbB-1 and The majority of ovarian cancer patients are treated with HER-1), erbB-2 (HER-2), erbB-3 (HER-3), and erbB-4 (HER-4; refs. platinum-based chemotherapy, but the emergence of resistance 6, 7). Ligands of the EGF family, including transforming growth factor-a (TGFa), activate the EGFR, whereas members of the to such chemotherapy severely limits its overall effectiveness. We have shown that development of resistance to this neuregulin (NRG)/heregulin family activate erbB-3 and erbB-4 (6). treatment can modify cell signaling responses in a model ErbB-2 is activated via interaction with other ligand-stimulated system wherein cisplatin treatment has altered cell respon- family members. Ligand binding to EGFR promotes either siveness to ligands of the erbB receptor family. A cisplatin- dimerization with another EGFR (homodimerization) or binding resistant ovarian carcinoma cell line PE01CDDP was derived to another erbB receptor family member (heterodimerization) in from the parent PE01 line by exposure to increasing concen- which case, erbB2 is the preferred option (7). The erbB receptor trations of cisplatin, eventually obtaining a 20-fold level of family are widely reported to have key roles in regulating a network resistance. Whereas PE01 cells were growth stimulated by the of signaling pathways, including the Ras/Raf/mitogen-activated erbB receptor-activating ligands, such as transforming growth protein kinase kinase (MEK)/extracellular signal-regulated kinase factor-A (TGFA), NRG1A, and NRG1B, the PE01CDDP line was (ERK) pathway (8), the phosphatidylinositol 3-kinase (PI3K)/Akt g growth inhibited by TGFA and NRG1B but unaffected by pathway (9), and the PLC cascades (10). These are implicated in NRG1A. TGFA increased apoptosis in PE01CDDP cells but the translation of ligand-mediated signaling at the cell membrane to the nucleus where induction of gene expression provides the decreased apoptosis in PE01 cells. Differences in extracellular signal-regulated kinase and phosphatidylinositol 3-kinase basis for the cell response. In response to external stimuli, cells may signaling were also found, which may be implicated in the be directed to grow, differentiate, migrate, or apoptose; outcomes altered cell response to ligands. Microarray analysis revealed which will ultimately determine the rate and the manner in which 51 genes whose mRNA increased by at least 2-fold in PE01CDDP the disease will progress and also how it will respond to treatment. cells relative to PE01 (including FRA1, ETV4, MCM2, AXL, MT3, The erbB receptors and their ligands play key roles in the growth TRAP1, and FANCG), whereas 36 genes (including IGFBP3, and progression of several cancers including ovarian cancer (6, 11). TRAM1, and KRT4 and KRT19) decreased by a similar amount. Overexpression of both EGFR and erbB2 separately have been Differential display reverse transcriptase-PCR identified al- linked to poor survival in ovarian cancer (12–15) and EGFR tered mRNA expression for TCP1, SLP1, proliferating cell activators are mitogens in ovarian cancer cell lines in culture (16–18). Several EGFR-targeted inhibitors are currently being nuclear antigen, and ZXDA. Small interfering RNA inhibition of FRA1, TCP1,andMCM2 expression was associated with considered for evaluation in advanced ovarian cancer and the reduced growth and FRA1 inhibition with enhanced cisplatin effect of prior treatment with cisplatin on the signaling pathways sensitivity. Altered expression of these genes by cytotoxic may be important in influencing tumor response. These agents exposure may provide survival advantages to cells including include the tyrosine kinase inhibitors gefitinib (‘‘Iressa’’; ZD 1839; deregulation of signaling pathways, which may be critical in the refs. 19, 20) and erlotinib (‘‘Tarceva’’; OSI-774; ref. 21). To understand further the changes in EGF signaling after the development of drug resistance. (Cancer Res 2005; 65(15): 6789-800) onset of cisplatin resistance, we have developed an in vitro model wherein the parent cell line PE01 has been made resistant to Introduction cisplatin by exposure to increasing levels of drug. Coupled with this Platinum-based chemotherapy is a standard first-line treatment change in drug sensitivity is a modified responsiveness to ligands of for ovarian cancer (1). In many instances, however, resistance to the erbB receptor family. In this report, we have identified a chemotherapy develops, limiting its use. The changes in cellular number of changes that might be significant in explaining the signaling after drug treatment are currently attracting a great deal altered phenotype. of interest and this is of particular relevance when cytotoxic therapy is combined with signaling inhibitors. Among the key regulators of growth in this disease is the group 1 receptor tyrosine Materials and Methods kinase family of erbB receptors. Cisplatin is known to interact with Cell lines and culture conditions. The PE01 cell line was derived from the epidermal growth factor receptor (EGFR) pathway (2) either a poorly differentiated human ovarian adenocarcinoma (22). The PE01CDDP promoting (3, 4) or inhibiting apoptosis and cell death (5). variant was established by in vitro exposure of the PE01 line to cisplatin commencing at 25 nmol/L cisplatin and increasing to 1 Amol/L over a period of 4 months. The resistant cell line thus obtained was then passaged Requests for reprints: Simon P. Langdon, Cancer Research UK Centre, University in the absence of cisplatin for a further 4 months to ensure that the of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, United Kingdom. Phone: 44- 131-777-3537; Fax: 44-131-777-3520; E-mail: [email protected]. resistance remained stable. Both cell lines were maintained in RPMI 1640 I2005 American Association for Cancer Research. (Life Technologies, Paisley, Scotland) containing 10% heat-inactivated FCS, www.aacrjournals.org 6789 Cancer Res 2005; 65: (15). August 1, 2005 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2005 American Association for Cancer Research. Cancer Research penicillin (100 units/mL), and streptomycin (100 Ag/mL). Cells were left for 24 hours. Medium was changed every 2 to 3 days for 12 to 14 days j maintained routinely at 37 C in a humidified atmosphere of 5% CO2 in air. until colonies (>50 cells) were obtained in the untreated control wells. The Growth assays. Cells in log-phase growth were seeded in 24-well plates surviving fraction in each of the drug-treated samples was then counted (Falcon, Franklin Lakes, NJ) at a density of 2.5 Â 104 cells per well in using an inverted microscope and the colony counts obtained for drug- quadruplicate in RPMI 1640 containing 10% heat-inactivated FCS, penicillin treated wells expressed as a percentage of the counts in untreated control (100 units/mL), and streptomycin (100 Ag/mL). After 24 hours, medium was wells. Dose-response curves were plotted for each drug-cell line combina- replaced by phenol red-free RPMI 1640 containing 5% double charcoal- tion and IC50 values extrapolated from summed data obtained from at least stripped FCS (DCS-FCS), penicillin (100 units/mL), streptomycin (100 Ag/ three experiments in every case. Cytotoxic drugs were obtained from the mL), and glutamine (2 mmol/L). After a further 24 hours, medium was following sources: Carboplatin (CBDCA) and iproplatin (CHIP) were gifts removed and replenished. Ligand additions were made at this time point, from Dr. Mervyn Jones (Institute of Cancer Research, Sutton, United designated day 0, and medium plus additions was replaced on day 2. In Kingdom); cisplatin and JM40 were obtained from Bristol Myers certain experiments, inhibitors were also added alongside ligands. Cells Pharmaceuticals; chlorambucil and melphalan from Sigma; doxorubicin were harvested on days 0, 2, and 5 and counted using a cell counter (Coulter from Farmitalia Carlo Erba Ltd.; and prednimustine from Aktiebolaget Leo Electronics, Ltd., Luton, England). TGFa and EGF were obtained from (Helsingborg, Sweden). Boehringer Mannheim (Indianapolis, IN), NRG1a from Sigma Ltd. (St. Louis, Apoptosis assay. PE01 and PE01CDDP cells were grown to 80% MO), and NRG1h from Neomarkers (Fremont, CA). Gefitinib was a gift from confluence in the presence of RPMI 1640 containing 10% FCS. Following AstraZeneca (Macclesfield, United Kingdom) and LY294002 (40202) and an overnight incubation in phenol red–free RPMI 1640 containing 5% DCS- PD98059 (513000) were obtained from Calbiochem (La Jolla, CA). FCS, the medium was replenished before the addition of TGFa. Apoptosis Clonogenic assay. Cells in logarithmic growth were plated in 35-mm was measured using the TACS Annexin V-FITC kit (R&D Systems, 6-well plates (Costar, Cambridge, MA) at densities that produced 100 to 200 Minneapolis, MN) following the prescribed protocol. colonies in untreated wells (2 Â 103/mL for PE01 and 103/mL for PE01CDDP mRNA extraction and reverse transcriptase-PCR. Total cellular RNA cells). The medium described above was used but with the addition of was extracted from cells in log-phase growth using TRI reagent (Sigma, 1 mmol/L sodium pyruvate to enhance plating at low cell densities.
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