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Updated: Jun 9, 2025
Analysis of Cell Cycle Position in Mammalian Cells
Published on: January 21, 2012
RRM2 inhibition alters cell cycle through ATM/Rb/E2F1 pathway in atypical teratoid rhabdoid tumor
Le Hien Giang1, Kuo-Sheng Wu2, Wei-Chung Lee3
1International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Department of Biology and Genetics, Hai Phong University of Medicine and Pharmacy, Hai Phong 180000, Vietnam.
Background:
Atypical teratoid rhabdoid tumor (ATRT) is an aggressive brain tumor that mainly affects young children. Our recent study reported a promising therapeutic strategy to trigger DNA damage, impede homologous recombination repair, and induce apoptosis in ATRT cells by targeting ribonucleotide reductase regulatory subunit M2 (RRM2). COH29, an inhibitor of RRM2, effectively reduced tumor growth and prolonged survival in vivo. Herein, we explored the underlying mechanisms controlling these functions to improve the clinical applicability of COH29 in ATRT.
Methods:
Molecular profiling of ATRT patients and COH29-treated cells was analyzed to identify the specific signaling pathways, followed by validation using a knockdown system, flow cytometry, q-PCR, and western blot.
Results:
Elevated E2F1 and its signaling pathway were correlated with poor prognosis. RRM2 inhibition induced DNA damage and activated ATM, which reduced Rb phosphorylation to promote Rb-E2F1 interaction and hindered E2F1 functions. E2F1 activity suppression led to decreased E2F1-dependent target expressions, causing cell cycle arrest in the G1 phase, decreased S phase cells, and blocked DNA damage repair.
Conclusion:
Our study highlights the role of ATM/Rb/E2F1 pathway in controlling cell cycle arrest and apoptosis in response to RRM2 inhibition-induced DNA damage. This provides insight into the therapeutic benefits of COH29 and suggests targeting this pathway as a potential treatment for ATRT.
Insights
Targeting ribonucleotide reductase regulatory subunit M2 (RRM2) with COH29 induces DNA damage and cell cycle arrest in atypical teratoid rhabdoid tumors (ATRT). This RRM2 inhibition impacts the ATM/Rb/E2F1 pathway, offering a potential new ATRT treatment.
Area of Science:
- Pediatric oncology
- Molecular biology
- Cancer research
Background:
- Atypical teratoid rhabdoid tumor (ATRT) is a rare and aggressive pediatric brain cancer.
- Targeting ribonucleotide reductase regulatory subunit M2 (RRM2) with COH29 shows promise in ATRT treatment by inducing DNA damage and apoptosis.
- Understanding the mechanisms of COH29 action is crucial for its clinical application in ATRT.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying the therapeutic effects of COH29 in ATRT.
- To identify key signaling pathways modulated by RRM2 inhibition in ATRT cells.
- To explore the potential of targeting the ATM/Rb/E2F1 pathway for ATRT treatment.
Main Methods:
- Molecular profiling of ATRT patient samples and COH29-treated cells.
- Validation using knockdown systems, flow cytometry, quantitative PCR (q-PCR), and western blot analysis.
- Analysis of the ATM/Rb/E2F1 signaling pathway.
Main Results:
- Elevated E2F1 expression correlates with poor prognosis in ATRT.
- RRM2 inhibition by COH29 triggers DNA damage and activates ATM.
- ATM activation leads to reduced Rb phosphorylation, promoting Rb-E2F1 interaction and inhibiting E2F1 activity, resulting in cell cycle arrest and impaired DNA repair.
Conclusions:
- The ATM/Rb/E2F1 pathway is critical in mediating cell cycle arrest and apoptosis following RRM2 inhibition-induced DNA damage in ATRT.
- COH29's therapeutic benefits in ATRT are linked to its modulation of the ATM/Rb/E2F1 pathway.
- Targeting this pathway presents a potential therapeutic strategy for ATRT.
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