Abstract
BackgroundRoutine chemotherapy often cannot achieve good therapeutic effects because of multidrug resistance (MDR). MDR is frequently caused by the elevated expression of the MDR1 gene encoding P-glycoprotein (P-gp). E2F1 is a frequently overexpressed protein in human tumor cells that increases the activity of the MDR1 promoter, resulting in higher P-gp levels. The upregulation of P-gp might contribute to the survival of tumor cells during chemotherapy. E2F1 confers anticancer drug resistance; however, we speculate whether E2F1 affects MDR through other pathways. This study investigated the possible involvement of E2F1 in anticancer drug resistance of gastric carcinoma in vitro and in vivo.MethodsA cisplatin-resistant SGC7901/DDP gastric cancer cell line with stable overexpression of E2F1 was established. Protein expression levels of E2F1, MDR1, MRP, TAp73, GAX, ZEB1, and ZEB2 were detected by western blotting. The influence of overexpression of E2F1 on anticancer drug resistance was assessed by measuring IC50 of SGC7901/DDP cells to cisplatin, doxorubicin, and 5-fluorouracil, as well as the rate of doxorubicin efflux, apoptosis, and cell cycle progression detected by flow cytometry. We determined the in vivo effects of E2F1-overexpression on tumor size in nude mice, and apoptotic cells in tumor tissues were detected by deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling and hematoxylin and eosin staining.ResultsThe SGC7901/DDP gastric cancer cell line stably overexpressing E2F1 exhibited significantly inhibited sensitivity to cisplatin, doxorubicin, and 5-fluorouracil. Flow cytometry confirmed that the percentage of apoptotic cells decreased after E2F1 upregulation, and that upregulation of E2F1 potentiated S phase arrest of the cell cycle. Furthermore, upregulation of E2F1 significantly decreased intracellular accumulation of doxorubicin. Western blot revealed that E2F1 upregulation suppressed expression of GAX, and increased the expression of MDR1, MRP, ZEB1, TAp73, and ZEB2.ConclusionsOverexpression of E2F1 promotes the development of MDR in gastric carcinoma, suggesting that E2F1 may represent an efficacious target for gastric cancer therapy.
Highlights
Routine chemotherapy often cannot achieve good therapeutic effects because of multidrug resistance (MDR)
Upregulation of E2F1 is associated with development of MDR in gastric carcinoma To examine the relationship between upregulation of E2F1 and acquisition of MDR in gastric carcinoma, we established gastric carcinoma cells that stably overexpressed E2F1
Most chemotherapeutic agents applied in the treatment of hematologic malignancies can induce apoptosis, but MDR tumor cells are generally resistant to apoptosis induction [12]
Summary
Routine chemotherapy often cannot achieve good therapeutic effects because of multidrug resistance (MDR). E2F1 is a frequently overexpressed protein in human tumor cells that increases the activity of the MDR1 promoter, resulting in higher P-gp levels. This study investigated the possible involvement of E2F1 in anticancer drug resistance of gastric carcinoma in vitro and in vivo. A previous study reported that deregulated E2F1 acts as a driving force in melanoma progression and promotes tumor invasion and metastasis independently from its other cellular activities. This aggressive behavior of the transcription factor in malignant cells is partially mediated through the induction of the epidermal growth factor receptor pathway [5]. This evidence implies that E2F1 is associated with carcinogenesis and development of MDR, the precise role of E2F1 in MDR of gastric carcinoma remains largely unexplored
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