PNPO‐Mediated Oxidation of DVL3 Promotes Multiple Myeloma Malignancy and Osteoclastogenesis by Activating the Wnt/β‐Catenin Pathway
Abstract 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 signi...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-02-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202407681 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832540884203208704 |
|---|---|
| author | Zhendong Deng Shanliang Sun Nian Zhou Yumeng Peng Long Cheng Xichao Yu Yuxia Yuan Mengjie Guo Min Xu Yuexin Cheng Fan Zhou Nianguang Li Ye Yang Chunyan Gu |
| author_facet | Zhendong Deng Shanliang Sun Nian Zhou Yumeng Peng Long Cheng Xichao Yu Yuxia Yuan Mengjie Guo Min Xu Yuexin Cheng Fan Zhou Nianguang Li Ye Yang Chunyan Gu |
| author_sort | Zhendong Deng |
| collection | DOAJ |
| description | Abstract 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 3M282 (DVL3), leading to abnormal activation of the Wnt/β‐catenin pathway. Based on the critical sites of PNPOR95/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. |
| format | Article |
| id | doaj-art-29f16da010be442c8523d1a56b1726c6 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-29f16da010be442c8523d1a56b1726c62025-02-04T13:14:54ZengWileyAdvanced Science2198-38442025-02-01125n/an/a10.1002/advs.202407681PNPO‐Mediated Oxidation of DVL3 Promotes Multiple Myeloma Malignancy and Osteoclastogenesis by Activating the Wnt/β‐Catenin PathwayZhendong Deng0Shanliang Sun1Nian Zhou2Yumeng Peng3Long Cheng4Xichao Yu5Yuxia Yuan6Mengjie Guo7Min Xu8Yuexin Cheng9Fan Zhou10Nianguang Li11Ye Yang12Chunyan Gu13Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine Nanjing 210022 ChinaNational and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine Nanjing University of Chinese Medicine Nanjing 210023 ChinaDepartment of Hematology and Oncology Jing'an District Zhabei Central Hospital Shanghai 200070 ChinaSchool of Medicine Nanjing University of Chinese Medicine Nanjing 210023 ChinaSchool of Medicine Nanjing University of Chinese Medicine Nanjing 210023 ChinaSchool of Medicine Nanjing University of Chinese Medicine Nanjing 210023 ChinaSchool of Medicine Nanjing University of Chinese Medicine Nanjing 210023 ChinaSchool of Medicine Nanjing University of Chinese Medicine Nanjing 210023 ChinaYangtze River Delta County Hematology Union Shanghai 200070 ChinaYangtze River Delta County Hematology Union Shanghai 200070 ChinaDepartment of Hematology and Oncology Jing'an District Zhabei Central Hospital Shanghai 200070 ChinaNational and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine Nanjing University of Chinese Medicine Nanjing 210023 ChinaSchool of Medicine Nanjing University of Chinese Medicine Nanjing 210023 ChinaNanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine Nanjing 210022 ChinaAbstract 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 3M282 (DVL3), leading to abnormal activation of the Wnt/β‐catenin pathway. Based on the critical sites of PNPOR95/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.https://doi.org/10.1002/advs.202407681dishevelled 3eltrombopagmultiple myelomapyridoxine‐5′‐phosphate oxidasewnt/β‐catenin pathway |
| spellingShingle | Zhendong Deng Shanliang Sun Nian Zhou Yumeng Peng Long Cheng Xichao Yu Yuxia Yuan Mengjie Guo Min Xu Yuexin Cheng Fan Zhou Nianguang Li Ye Yang Chunyan Gu PNPO‐Mediated Oxidation of DVL3 Promotes Multiple Myeloma Malignancy and Osteoclastogenesis by Activating the Wnt/β‐Catenin Pathway Advanced Science dishevelled 3 eltrombopag multiple myeloma pyridoxine‐5′‐phosphate oxidase wnt/β‐catenin pathway |
| title | PNPO‐Mediated Oxidation of DVL3 Promotes Multiple Myeloma Malignancy and Osteoclastogenesis by Activating the Wnt/β‐Catenin Pathway |
| title_full | PNPO‐Mediated Oxidation of DVL3 Promotes Multiple Myeloma Malignancy and Osteoclastogenesis by Activating the Wnt/β‐Catenin Pathway |
| title_fullStr | PNPO‐Mediated Oxidation of DVL3 Promotes Multiple Myeloma Malignancy and Osteoclastogenesis by Activating the Wnt/β‐Catenin Pathway |
| title_full_unstemmed | PNPO‐Mediated Oxidation of DVL3 Promotes Multiple Myeloma Malignancy and Osteoclastogenesis by Activating the Wnt/β‐Catenin Pathway |
| title_short | PNPO‐Mediated Oxidation of DVL3 Promotes Multiple Myeloma Malignancy and Osteoclastogenesis by Activating the Wnt/β‐Catenin Pathway |
| title_sort | pnpo mediated oxidation of dvl3 promotes multiple myeloma malignancy and osteoclastogenesis by activating the wnt β catenin pathway |
| topic | dishevelled 3 eltrombopag multiple myeloma pyridoxine‐5′‐phosphate oxidase wnt/β‐catenin pathway |
| url | https://doi.org/10.1002/advs.202407681 |
| work_keys_str_mv | AT zhendongdeng pnpomediatedoxidationofdvl3promotesmultiplemyelomamalignancyandosteoclastogenesisbyactivatingthewntbcateninpathway AT shanliangsun pnpomediatedoxidationofdvl3promotesmultiplemyelomamalignancyandosteoclastogenesisbyactivatingthewntbcateninpathway AT nianzhou pnpomediatedoxidationofdvl3promotesmultiplemyelomamalignancyandosteoclastogenesisbyactivatingthewntbcateninpathway AT yumengpeng pnpomediatedoxidationofdvl3promotesmultiplemyelomamalignancyandosteoclastogenesisbyactivatingthewntbcateninpathway AT longcheng pnpomediatedoxidationofdvl3promotesmultiplemyelomamalignancyandosteoclastogenesisbyactivatingthewntbcateninpathway AT xichaoyu pnpomediatedoxidationofdvl3promotesmultiplemyelomamalignancyandosteoclastogenesisbyactivatingthewntbcateninpathway AT yuxiayuan pnpomediatedoxidationofdvl3promotesmultiplemyelomamalignancyandosteoclastogenesisbyactivatingthewntbcateninpathway AT mengjieguo pnpomediatedoxidationofdvl3promotesmultiplemyelomamalignancyandosteoclastogenesisbyactivatingthewntbcateninpathway AT minxu pnpomediatedoxidationofdvl3promotesmultiplemyelomamalignancyandosteoclastogenesisbyactivatingthewntbcateninpathway AT yuexincheng pnpomediatedoxidationofdvl3promotesmultiplemyelomamalignancyandosteoclastogenesisbyactivatingthewntbcateninpathway AT fanzhou pnpomediatedoxidationofdvl3promotesmultiplemyelomamalignancyandosteoclastogenesisbyactivatingthewntbcateninpathway AT nianguangli pnpomediatedoxidationofdvl3promotesmultiplemyelomamalignancyandosteoclastogenesisbyactivatingthewntbcateninpathway AT yeyang pnpomediatedoxidationofdvl3promotesmultiplemyelomamalignancyandosteoclastogenesisbyactivatingthewntbcateninpathway AT chunyangu pnpomediatedoxidationofdvl3promotesmultiplemyelomamalignancyandosteoclastogenesisbyactivatingthewntbcateninpathway |