RRM2 inhibition alters cell cycle through ATM/Rb/E2F1 pathway in atypical teratoid rhabdoid tumor.

Autor:	Giang LH; International 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., Wu KS; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan., Lee WC; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan., Chu SS; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan., Do AD; International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; Department of Physiology, Pathophysiology and Immunology, Pham Ngoc Thach University of Medicine, Ho Chi Minh City 700000, Vietnam., Huang MH; Department of Pathology, Shuang-Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan., Lin YL; Agricultural Biotechnology Research Center, Academia Sinica, Taipei 115, Taiwan., Hsieh CL; The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; General Clinical Research Center, Chung Shan Medical University Hospital, Taichung 402, Taiwan., Sung SY; International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan., Yen Y; The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan., Wong TT; Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Pediatric Brain Tumor Program, Taipei Cancer Center, Taipei Medical University, Taipei 110, Taiwan; Division of Pediatric Neurosurgery, Department of Neurosurgery, Taipei Medical University Hospital and Taipei Neuroscience Institute, Taipei Medical University, Taipei 110, Taiwan; Neuroscience Research Center, Taipei Medical University Hospital, Taipei 110, Taiwan; TMU Research Center for Cancer Translational Medicine, Taipei Medical University, Taipei 110, Taiwan. Electronic address: ttwong99@gmail.com., Chang CC; International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; Neuroscience Research Center, Taipei Medical University Hospital, Taipei 110, Taiwan; TMU Research Center for Cancer Translational Medicine, Taipei Medical University, Taipei 110, Taiwan; Master Program in Clinical Genomics and Proteomics, School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan; Traditional Herbal Medicine Research Center of Taipei Medical University Hospital, Taipei 11031, Taiwan. Electronic address: ccchang168@tmu.edu.tw.
Jazyk:	angličtina
Zdroj:	Neoplasia (New York, N.Y.) [Neoplasia] 2024 Dec; Vol. 58, pp. 101075. Date of Electronic Publication: 2024 Oct 21.
DOI:	10.1016/j.neo.2024.101075
Abstrakt:	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. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024. Published by Elsevier Inc.)
Databáze:	MEDLINE
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