Inhibition of IRP2-dependent reprogramming of iron metabolism suppresses tumor growth in colorectal cancer.

Autor: Hwang J; Department of Medicine, Yonsei University College of Medicine, Seoul, 03722, Korea.; Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, 03722, Korea., Park A; Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Korea.; Department of Chemistry, Yonsei University, Seoul, 03722, Korea., Kim C; Department of Medicine, Yonsei University College of Medicine, Seoul, 03722, Korea.; Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, 03722, Korea., Kim CG; Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, 03722, Korea., Kwak J; Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Korea., Kim B; Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Korea., Shin H; Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Korea., Ku M; Department of Radiology, Yonsei University College of Medicine, Seoul, 03722, Korea.; Convergence Research Center for Systems Molecular Radiological Science, Yonsei University, Seoul, 03722, Korea., Yang J; Department of Radiology, Yonsei University College of Medicine, Seoul, 03722, Korea.; Convergence Research Center for Systems Molecular Radiological Science, Yonsei University, Seoul, 03722, Korea., Baek A; Bioinformatics and Molecular Design Research Center, Incheon, 21983, Korea., Choi J; College of Pharmacy, Dongduk Women's University, Seoul, 02748, Korea., Lim H; Bioinformatics and Molecular Design Research Center, Incheon, 21983, Korea., No KT; Bioinformatics and Molecular Design Research Center, Incheon, 21983, Korea.; The Interdisciplinary Graduate Program in Integrative Biotechnology & Translational Medicine, Yonsei Unversity, Incheon, 21983, Korea., Zhao X; Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, 03722, Korea., Choi U; Department of Medicine, Yonsei University College of Medicine, Seoul, 03722, Korea.; Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, 03722, Korea., Kim TI; Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 03722, Korea., Jeong KS; Department of Chemistry, Yonsei University, Seoul, 03722, Korea., Lee H; Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Korea. leeh@krict.re.kr., Shin SJ; Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, 03722, Korea. ssj338@yuhs.ac.; Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, 03722, Korea. ssj338@yuhs.ac.; Convergence Research Center for Systems Molecular Radiological Science, Yonsei University, Seoul, 03722, Korea. ssj338@yuhs.ac.
Jazyk: angličtina
Zdroj: Cell communication and signaling : CCS [Cell Commun Signal] 2024 Aug 23; Vol. 22 (1), pp. 412. Date of Electronic Publication: 2024 Aug 23.
DOI: 10.1186/s12964-024-01769-6
Abstrakt: Background: Dysregulation of iron metabolism is implicated in malignant transformation, cancer progression, and therapeutic resistance. Here, we demonstrate that iron regulatory protein 2 (IRP2) preferentially regulates iron metabolism and promotes tumor growth in colorectal cancer (CRC).
Methods: IRP2 knockdown and knockout cells were generated using RNA interference and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 methodologies, respectively. Cell viability was evaluated using both CCK-8 assay and cell counting techniques. Furthermore, IRP2 inhibition was determined by surface plasmon resonance (SPR) and RNA immunoprecipitation (IP). The suppressive effects of IRP2 were also corroborated in both organoid and mouse xenograft models, providing a comprehensive validation of IRP2's role.
Results: We have elucidated the role of IRP2 as a preferential regulator of iron metabolism, actively promoting tumorigenesis within CRC. Elevated levels of IRP2 expression in patient samples are correlated with diminished overall survival, thereby reinforcing its potential role as a prognostic biomarker. The functional suppression of IRP2 resulted in a pronounced delay in tumor growth. Building on this proof of concept, we have developed IRP2 inhibitors that significantly reduce IRP2 expression and hinder its interaction with iron-responsive elements in key iron-regulating proteins, such as ferritin heavy chain 1 (FTH1) and transferrin receptor (TFRC), culminating in iron depletion and a marked reduction in CRC cell proliferation. Furthermore, these inhibitors are shown to activate the AMPK-ULK1-Beclin1 signaling cascade, leading to cell death in CRC models.
Conclusions: Collectively, these findings highlight the therapeutic potential of targeting IRP2 to exploit the disruption of iron metabolism in CRC, presenting a strategic advancement in addressing a critical area of unmet clinical need.
(© 2024. The Author(s).)
Databáze: MEDLINE
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