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Updated: Jun 4, 2026
Development and Application of Rapamycin-regulated Tyrosine Phosphatases
Published on: September 6, 2024
Targeting the autophagy pathway using ectopic expression of Beclin 1 in combination with rapamycin in drug-resistant
1Division of Life Sciences, College of Natural Sciences, University of Incheon, Incheon, 406-772, Korea.
Abstract:
The effectiveness of an apoptosis-targeting therapy may be limited in tumor cells with defects in apoptosis. Recently, considerable attention in the field of cancer therapy has been focused on the mammalian rapamycin target (mTOR), inhibition of which results in autophagic cell death. In our study using multidrug-resistant v-Ha-ras-transformed NIH3T3 (Ras-NIH 3T3/Mdr) cells, we demonstrated that rapamycin-induced cell death may result from 2 different mechanisms. At high rapamycin concentrations (≥ 100 nM), cell death may occur via an autophagy-dependent pathway, whereas at lower concentrations (≤ 10 nM), cell death may occur after G1-phase cell cycle arrest. This effect was accompanied by upregulation of p21(Cip1) and p27(Kip1) expression via an autophagy-independent pathway. We also tested whether inhibition of mTOR with low concentrations of rapamycin and ectopic Beclin-1 expression would further sensitize multidrug resistance (MDR)-positive cancer cells by upregulating autophagy. Rapamycin at low concentrations might be insufficient to initiate autophagosome formation in autophagy but Beclin-1 overexpression triggered additional processes downstream of mTOR during G(1) cell cycle arrest by rapamycin. Our findings suggest that these combination strategies targeting autophagic cell death may yield significant benefits for cancer patients, because lowering rapamycin concentration for cancer treatment minimizes its side effects in patients undergoing chemotherapy.
Insights
Rapamycin at high concentrations induces cancer cell death via autophagy, while low concentrations cause cell cycle arrest. Combining low-dose rapamycin with Beclin-1 enhances autophagy and may reduce chemotherapy side effects.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Apoptosis-targeting therapies can be ineffective in cancer cells with defective apoptosis.
- Mammalian target of rapamycin (mTOR) inhibition is a focus in cancer therapy, potentially inducing autophagic cell death.
Purpose of the Study:
- To investigate the mechanisms of rapamycin-induced cell death in multidrug-resistant (MDR) cancer cells.
- To explore the potential of combining low-dose rapamycin with Beclin-1 to enhance autophagy and sensitize MDR cancer cells.
Main Methods:
- Utilized multidrug-resistant v-Ha-ras-transformed NIH3T3 (Ras-NIH 3T3/Mdr) cells.
- Administered varying concentrations of rapamycin (high: ≥ 100 nM, low: ≤ 10 nM).
- Assessed cell death pathways (autophagy-dependent/independent) and cell cycle arrest, including p21(Cip1) and p27(Kip1) expression. Evaluated effects of Beclin-1 overexpression.
Main Results:
- High rapamycin concentrations (≥ 100 nM) induced cell death via autophagy.
- Low rapamycin concentrations (≤ 10 nM) induced G1-phase cell cycle arrest through an autophagy-independent pathway, upregulating p21(Cip1) and p27(Kip1).
- Combining low-dose rapamycin with Beclin-1 overexpression enhanced autophagy and downstream processes during G1 arrest.
Conclusions:
- Rapamycin exhibits dual mechanisms for cancer cell death dependent on concentration.
- Low-dose rapamycin combined with Beclin-1 may represent a strategy to sensitize MDR cancer cells by enhancing autophagy.
- This combination approach could offer therapeutic benefits by minimizing rapamycin's side effects in patients.
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