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Published on: May 1, 2020
The 4E-BP1/eIF4E ratio is a determinant for rapamycin response in esophageal cancer cells
Han-Shui Hsu1, Ming-Hsien Lin2, Yi-Hua Jang3
1Institute of Emergency and Critical Care Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
Objectives:
Rapamycin inhibits products of molecular pathways in esophageal squamous cell carcinoma and limits tumor cell growth by targeting 4E-BP1- and eIF4E-dependent gene translation. In this study, we investigate the influence of 4E-BP1-to-eIF4E ratio on rapamycin response in esophageal squamous cell carcinoma cells, and the underlying mechanism is discussed.
Methods:
The response to rapamycin treatment was examined in 6 esophageal cancer cell lines. Adjustment of the 4E-BP1/eIF4E ratio was carried out by knockdown or overexpression of 4E-BP1 and eIF4E. The relationship between Egr-1 and 4E-BP1 expression in esophageal cancer cells was also studied.
Results:
The 4E-BP1/eIF4E ratio was adjusted to evaluate the response to rapamycin treatment in TE1 and TE2 esophageal cancer cells. TE2 cells are sensitized to rapamycin treatment after overexpression of 4E-BP1 or knockdown of eIF4E; TE1 cells become resistant to rapamycin after knockdown of 4E-BP1 or overexpression of eIF4E. These data suggest that the 4E-BP1/eIF4E ratio is a determinant for the response of TE1 and TE2 cells to rapamycin treatment. Egr-1 expression was higher in TE2 cells compared with other esophageal cancer cell lines, and its knockdown increased 4E-BP1 expression in TE2 cells, which became sensitive to rapamycin treatment.
Conclusions:
The 4E-BP1/eIF4E ratio is a determinant of the response of rapamycin treatment in esophageal cancer cells. Egr-1 can reduce 4E-BP1 gene expression and render esophageal squamous cell carcinoma cells resistant to rapamycin with a relatively low 4E-BP1/eIF4E ratio. Thus, the 4E-BP1/eIF4E ratio may represent a therapeutic index for the prediction of clinical outcome of rapamycin treatment in patients with esophageal squamous cell carcinoma.
Insights
The 4E-BP1/eIF4E ratio determines how esophageal cancer cells respond to rapamycin. This ratio, influenced by Egr-1, could predict treatment outcomes in patients with esophageal squamous cell carcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Rapamycin is an mTOR inhibitor impacting gene translation.
- It targets 4E-BP1 and eIF4E in esophageal squamous cell carcinoma (ESCC).
- Understanding factors influencing rapamycin response is crucial for effective cancer treatment.
Purpose of the Study:
- To investigate the role of the 4E-BP1/eIF4E ratio in rapamycin sensitivity in ESCC cells.
- To elucidate the underlying molecular mechanisms governing this response.
- To explore the potential of the 4E-BP1/eIF4E ratio as a predictive biomarker.
Main Methods:
- Examined rapamycin response in six ESCC cell lines.
- Manipulated 4E-BP1/eIF4E ratios via gene knockdown and overexpression.
- Assessed the relationship between Egr-1 and 4E-BP1 expression.
Main Results:
- The 4E-BP1/eIF4E ratio significantly influenced rapamycin sensitivity in TE1 and TE2 ESCC cells.
- Overexpressing 4E-BP1 or knocking down eIF4E sensitized cells to rapamycin.
- Knocking down Egr-1 increased 4E-BP1 expression and rapamycin sensitivity in TE2 cells.
Conclusions:
- The 4E-BP1/eIF4E ratio is a key determinant of rapamycin response in ESCC.
- Egr-1 downregulates 4E-BP1, potentially leading to rapamycin resistance.
- The 4E-BP1/eIF4E ratio may serve as a therapeutic index for predicting rapamycin efficacy in ESCC patients.
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