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Role of E2F-1 in chemosensitivity
D Banerjee1, B Schnieders, J Z Fu
1Molecular Pharmacology and Experimental Therapeutics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.
Abstract:
The E2F family of transcription factors, in partnership with DP proteins, is thought to regulate transcription of genes that encode protein products that are required for DNA synthesis, which include important cancer chemotherapeutic targets such as thymidylate synthase and dihydrofolate reductase. This study was conducted to investigate the effects of overexpression of human E2F-1 cDNA on chemosensitivity in a human fibrosarcoma cell line, HT-1080. The E2F-1-overexpressing HT-1080 cells had a shorter doubling time both in vitro and in vivo. Associated with an up-regulation of TS, E2F-1-transfected cells were more resistant to 5-fluorouracil than were untransfected cells. These E2F-1 transfectants, although resistant to fluoropyrimidines and serum deprivation, were more sensitive to etoposide, doxorubicin, and SN38 (the active metabolite of irinotecan) but not to Taxol.
Insights
Overexpressing E2F-1 in fibrosarcoma cells accelerated growth and altered chemosensitivity. E2F-1 increased resistance to 5-fluorouracil but enhanced sensitivity to etoposide and doxorubicin.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- The E2F family of transcription factors, with DP proteins, regulates genes essential for DNA synthesis.
- Key cancer drug targets like thymidylate synthase (TS) and dihydrofolate reductase are among these genes.
- Understanding E2F-1's role is crucial for developing targeted cancer therapies.
Purpose of the Study:
- To investigate the impact of human E2F-1 cDNA overexpression on chemosensitivity.
- To analyze the effects on cell proliferation and drug response in HT-1080 fibrosarcoma cells.
Main Methods:
- Overexpression of human E2F-1 cDNA in HT-1080 fibrosarcoma cells.
- Assessment of cell doubling time in vitro and in vivo.
- Evaluation of chemosensitivity to various chemotherapeutic agents.
Main Results:
- E2F-1 overexpression led to a reduced doubling time for HT-1080 cells.
- Up-regulation of thymidylate synthase (TS) was observed in E2F-1 transfected cells.
- Cells overexpressing E2F-1 showed increased resistance to 5-fluorouracil but enhanced sensitivity to etoposide, doxorubicin, and SN38, while remaining unaffected by Taxol.
Conclusions:
- E2F-1 overexpression influences cell proliferation and alters chemosensitivity profiles.
- The findings suggest a complex role for E2F-1 in mediating responses to different chemotherapeutic drugs.
- Targeting E2F-1 pathways may offer novel strategies for cancer treatment, depending on the drug regimen.