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Early Responses of the STAT3 Pathway to Platinum Drugs Are Associated with Cisplatin Resistance in Epithelial Ovarian Cancer

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Early Responses of the STAT3 Pathway to Platinum Drugs Are Associated with Cisplatin Resistance in Epithelial Ovarian Cancer Brazilian Journal of Medical and Biological Research (2013) 46: 650-658, http://dx.doi.org/10.1590/1414-431X20133003 ISSN 1414-431X Early responses of the STAT3 pathway to platinum drugs are associated with cisplatin resistance in epithelial ovarian cancer W.J. Sheng1, H. Jiang1, D.L. Wu2 and J.H. Zheng1 1Department of Obstetrics and Gynecology, The First Affiliated Hospital of Harbin Medical University, Harbin, China 2The Key Laboratory of Veterinary Public Health, Ministry of Agriculture, State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agriculture Sciences, Harbin, China Abstract Cisplatin resistance remains one of the major obstacles when treating epithelial ovarian cancer. Because oxaliplatin and nedaplatin are effective against cisplatin-resistant ovarian cancer in clinical trials and signal transducer and activator of transcription 3 (STAT3) is associated with cisplatin resistance, we investigated whether overcoming cisplatin resistance by oxaliplatin and nedaplatin was associated with the STAT3 pathway in ovarian cancer. Alamar blue, clonogenic, and wound healing assays, and Western blot analysis were used to compare the effects of platinum drugs in SKOV-3 cells. At an equitoxic dose, oxaliplatin and nedaplatin exhibited similar inhibitory effects on colony-forming ability and greater inhibition on cell motility than cisplatin in ovarian cancer. Early in the time course of drug administration, cisplatin increased the expression of pSTAT3 (Tyr705), STAT3a, VEGF, survivin, and Bcl-XL, while oxaliplatin and nedaplatin exhibited the opposite effects, and upregulated pSTAT3 (Ser727) and STAT3b. The STAT3 pathway responded early to platinum drugs associated with cisplatin resistance in epithelial ovarian cancer and provided a rationale for new therapeutic strategies to reverse cisplatin resistance. Key words: Epithelial ovarian cancer; Cisplatin; Oxaliplatin; Nedaplatin; STAT3 Introduction Epithelial ovarian cancer accounts for approximately the mechanism underlying their reversal of cisplatin 90% of ovarian malignancies and is often discovered at an resistance remains largely unknown. Exposure to advanced stage, with a 5-year survival rate of less than chemotherapeutic agents can induce alterations in signal- 20% (1). While administration of cisplatin remains the ing cascades that mediate resistance (7). Among these, current standard of care in chemotherapy for this signal transducer and activator of transcription 3 (STAT3) malignancy, 75% of the patients eventually relapse (2). overexpression has been reported positively associated Cisplatin promotes development of drug resistance, thus with cisplatin resistance (8). there is an urgent need to overcome cisplatin resistance STAT3 is activated in 94% of ovarian cancers and is and identify its mechanisms. associated with more aggressive phenotypes (7-9). It also Nedaplatin, a second-generation platinum drug, has a correlates with recurrent tumors and poor prognosis higher water solubility than cisplatin and causes fewer (7-10). Furthermore, STAT3 participates in various side effects (3). Oxaliplatin, a third-generation platinum processes key to malignant progression: promoting cell compound, displays wide antitumor activity against proliferation, triggering tumor initiation, migration, inva- cancers restricted to the peritoneal cavity and showed sion, angiogenesis and metastasis, induction of epithelial- partial cross-resistance to cisplatin in preclinical studies mesenchymal transition (EMT), inhibition of apoptosis and (4). Both nedaplatin and oxaliplatin are effective in heavily cell cycle dysregulation, and promoting multidrug resis- pretreated ovarian cancer patients who are nonrespon- tance to chemotherapy (8-13). STAT3 also plays an sive to cisplatin, with manageable toxicity (4-6). However, important role in embryonic stem cells and the immune Correspondence: J.H. Zheng, 23 Youzheng Street, Nangang Block, Harbin, HLJ 150001, China. Fax: +86-451-8268-1772. E-mail: [email protected] Received February 4, 2013. Accepted May 23, 2013. First published online August 13, 2013. Braz J Med Biol Res 46(8) 2013 www.bjournal.com.br Early responses of the STAT3 pathway to platinum drugs 651 response (14,15) partially correlated with cancer progres- colonies divided by the number of control cells plated. sion. Targeting STAT3 may reverse the malignant progression described above. Wound healing assay Since oxaliplatin and nedaplatin have been effective Upon reaching 90% confluence on 6-well plates, cells against cisplatin-resistant ovarian cancer in clinical trials, were scraped across the cell monolayer using a sterile and targeting STAT3 may reverse drug resistance, we 200-mL pipette tip. After washing with PBS, cells were investigated whether the effects of platinum agents on the exposed to 1 mg/mL cisplatin, 8 mg/mL oxaliplatin, or 8 mg/mL STAT3 pathway were associated with cisplatin resistance. nedaplatin for 24 h. Cells that migrated to the wounded We observed that oxaliplatin and nedaplatin had various region were photographed at 0 h and again after 24 h. The effects on the STAT3 pathway that differed from that of wound area was quantified by Image J and estimated using cisplatin early in the course of treatment, which may the following equation: wound closure %=[1––(wound area contribute to elucidating their mechanisms of reversing at Tt/wound area at T0)6100%], where Tt is the elapsed cisplatin resistance. time after wounding and T0 is the time immediately after wounding. Material and Methods Western blot analysis Material Cells (16106) were seeded onto 6-well plates and Platinum drugs were from Aosaikang Pharmaceutical after treatment with 1 mg/mL cisplatin, 8 mg/mL oxaliplatin, Co., Ltd. (Nanjing, China). Alamar blue was purchased or 8 mg/mL nedaplatin at the indicated time, proteins were from Invitrogen (USA). RPMI 1640, FBS, antibiotics, and extracted using RIPA buffer complemented with PMSF. trypsin were from Gibco (USA). Nitrocellulose membranes The total protein concentration was determined by a BCA were from Amersham (UK). Primary antibodies were method. Equal amounts of total protein with 26SDS were purchased from Santa Cruz Biotechnology (USA), except separated on 10% SDS-polyacrylamide electrophoresis for pSTAT3 and Tyr705, which were from CST (USA). gels and transferred to nitrocellulose membranes by Secondary antibodies were from Dako (Denmark). semidry electrophoresis. The membranes were blocked Electrochemiluminescence (ECL) assay reagents were in 5% skim milk and incubated sequentially with the obtained from Pierce (USA). All other reagents and primary antibodies pSTAT3 (Tyr705), 1:1000; cyclin D1, compounds were of analytical grade. 1:100; vascular endothelial growth factor (VEGF), 1:100; others, 1:200), followed by a secondary peroxidase- Cell lines and cultures conjugated antibody (1:4000 dilution), and visualized with Human ovarian cancer SKOV-3 cells were from ATCC an ECL detection system. b-actin (1:500 dilution) was and cultured in RPMI 1640 medium with 10% FBS, 100 IU/mL used as the control protein. The results were quantified by penicillin, and 100 mg/mL streptomycin. Cells were cultured ImageJ and were normalized to that of b-actin to obtain at 376C in a humidified 5% CO2 atmosphere. relative intensity. Proliferation assay Statistical analysis SKOV-3 cells were seeded at 16103 cells/well on All statistical analyses were performed using GraphPad 96-well plates. Drugs were added at the indicated doses Prism 5.0 (USA). Statistical significance was analyzed by (n=6 for each experiment) 24 h after inoculation. The one-way ANOVA and the Dunnett post hoc test, with proliferation assay was performed 24, 48, and 72 h after values of P,0.05 considered to be statistically significant. drug treatment using the Alamar blue assay following the Data are reported as means±SE. Each experiment was manufacturer’s instructions. A microplate reader was repeated at least twice. used to measure the absorbance at 570 and 600 nm. Absorbance recordings were normalized to control cells Results and graphed as relative cell density. Equitoxic effects of platinum drugs in ovarian cancer Clonogenic assay cells At 24 h after exposure to 1 mg/mL cisplatin, 8 mg/mL We first evaluated the cytotoxic effects of cisplatin, oxaliplatin, or 8 mg/mL nedaplatin, SKOV-3 cells were oxaliplatin and nedaplatin in SKOV-3 cells, as their effects seeded at 1000 cells/well on 6-well plates. Cells were in ovarian cancer have not yet been compared. While cultured additionally for 10 days until visible colonies cisplatin (1 mg/mL) inhibited cell proliferation by approxi- formed. The cells were fixed with methanol and stained mately 40-50% by 48 h, oxaliplatin (8 mg/mL) and with 0.5% crystal violet in 2% ethanol for 10 min. The nedaplatin (8 mg/mL) demonstrated similar effects plates were washed 4 times with tap water and air-dried. (Figure 1). These equitoxic concentrations were used in Colonies comprising at least 50 cells were counted. The the subsequent experiments reported here in order to plating efficiencies were calculated as the number of exclude cytotoxic effects. www.bjournal.com.br Braz J Med Biol Res 46(8) 2013 652 W.J. Sheng et al. Figure 2. Effect of 1 mg/mL cisplatin, 8 mg/mL oxaliplatin, and 8 mg/mL nedaplatin on SKOV-3 cells in clonogenic assay. A, Photographs in a representative experiment are shown. B, The graph was calculated from the number of colonies formed on the culture plate 10 days after treatment. Clonogenic
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