PNPO-Mediated Oxidation of DVL3 Promotes Multiple Myeloma Malignancy and Osteoclastogenesis by Activating the Wnt/β-Catenin Pathway.

Autor: Deng Z; Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine, Nanjing, 210022, China.; School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Sun S; National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Zhou N; Department of Hematology and Oncology, Jing'an District Zhabei Central Hospital, Shanghai, 200070, China.; Yangtze River Delta County Hematology Union, Shanghai, 200070, China., Peng Y; School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Cheng L; School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Yu X; School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Yuan Y; School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Guo M; School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Xu M; Yangtze River Delta County Hematology Union, Shanghai, 200070, China.; Department of Hematology, Zhangjiagang First People's Hospital, Zhangjiagang, 215600, China., Cheng Y; Yangtze River Delta County Hematology Union, Shanghai, 200070, China.; Department of Hematology, Yancheng Clinical College of Xuzhou Medical University, Yancheng No.1 People's Hospital, Yancheng, 224006, China., Zhou F; Department of Hematology and Oncology, Jing'an District Zhabei Central Hospital, Shanghai, 200070, China.; Yangtze River Delta County Hematology Union, Shanghai, 200070, China., Li N; National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Yang Y; School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China., Gu C; Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine, Nanjing, 210022, China.; School of Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 Dec 10, pp. e2407681. Date of Electronic Publication: 2024 Dec 10.
DOI: 10.1002/advs.202407681
Abstrakt: Multiple myeloma (MM) is a cancer of plasma cells caused by abnormal gene expression and interactions within the bone marrow (BM) niche. The BM environment significantly influences the progression of MM. Celastrol, a natural compound derived from traditional Chinese medicine, exhibits significant anticancer effects. This study aimed to identify specific targets of celastrol and develop more effective and less toxic treatment options for MM. Celastrol is used as a probe to determine its specific target, pyridoxine-5'-phosphate oxidase (PNPO). Increased levels of PNPO are associated with poor outcomes in MM patients, and PNPO promotes MM cell proliferation and induces osteoclast differentiation through exosomes. Mechanistically, PNPO oxidizes disheveled 3 M282 (DVL3), leading to abnormal activation of the Wnt/β-catenin pathway. Based on the critical sites of PNPO R95/K117 , Eltrombopag is identified as a potential therapeutic candidate for MM. In addition, the experiments showed its efficacy in mouse models. Eltrombopag inhibited the growth of MM cells and reduced bone lesions by disrupting the interaction between PNPO and DVL3, as supported by preliminary clinical trials. The study highlights the importance of PNPO as a high-risk gene in the development of MM and suggests that Eltrombopag may be a promising treatment option.
(© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)
Databáze: MEDLINE
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