Platycodin D inhibits tumor proliferation by modulating macrophage polarization through promoting JAK2 ubiquitination
A growing body of evidence indicates that tumor-associated macrophages (TAMs) are crucial contributors to cancer progression, positioning them as an attractive target for therapeutic intervention. In our previous studies, we found that Platycodon grandiflorum exert anti-melanoma effects by influenci...
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Elsevier
2025-02-01
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| Series: | Journal of Functional Foods |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1756464625000131 |
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| author | Wei Wu Jie Zhang Zijiao Wang Chuan Cheng Dongdong Yuan Li Peng Le Li |
| author_facet | Wei Wu Jie Zhang Zijiao Wang Chuan Cheng Dongdong Yuan Li Peng Le Li |
| author_sort | Wei Wu |
| collection | DOAJ |
| description | A growing body of evidence indicates that tumor-associated macrophages (TAMs) are crucial contributors to cancer progression, positioning them as an attractive target for therapeutic intervention. In our previous studies, we found that Platycodon grandiflorum exert anti-melanoma effects by influencing TAMs. Platycodin D (PD), a bioactive compound derived from the dried roots of Platycodon grandiflorum, possesses anti-inflammatory, immunomodulatory, and anti-tumor properties. Based on this, we hypothesized that PD could have anti-melanoma potential and set out to investigate its molecular mechanisms in relation to TAMs. Treatment with PD led to a significant reduction in melanoma tumor weight, inhibition of the mTOR pathway, and suppression of M2-polarized macrophages. PD also downregulated M2 macrophage markers, impaired mitochondrial function, reduced ROS production, and diminished the tumor-promoting functions of TAMs. Through network pharmacology and experimental validation, STAT3 was identified as a central target. PD was shown to decrease JAK2 and p-STAT3 levels, promote JAK2 degradation, and enhance its ubiquitination. In Lyz2cre/cre JAK2flox/flox mice, which lack JAK2 specifically in bone marrow-derived macrophages (BMDMs) were resistant to PD's effects on M2 polarization, mitochondrial function, and melanoma suppression. In summary, PD inhibits melanoma growth by targeting JAK2, which in turn influences M2 polarization and mitochondrial function. This study underscores the potential of PD in regulating TAMs, providing new insights into its potential use in cancer therapy. |
| format | Article |
| id | doaj-art-687b3389b277455ab28128fed8d9d303 |
| institution | Kabale University |
| issn | 1756-4646 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Functional Foods |
| spelling | doaj-art-687b3389b277455ab28128fed8d9d3032025-02-09T04:59:55ZengElsevierJournal of Functional Foods1756-46462025-02-01125106671Platycodin D inhibits tumor proliferation by modulating macrophage polarization through promoting JAK2 ubiquitinationWei Wu0Jie Zhang1Zijiao Wang2Chuan Cheng3Dongdong Yuan4Li Peng5Le Li6Key Lab of Ministry of Education for Protection and Utilization of Special Biological Resources in Western China, School of Life Sciences, Ningxia University, Yinchuan 750021, China; Ningxia Chinese medicine Research Center, Yinchuan 750021, ChinaKey Lab of Ministry of Education for Protection and Utilization of Special Biological Resources in Western China, School of Life Sciences, Ningxia University, Yinchuan 750021, ChinaKey Lab of Ministry of Education for Protection and Utilization of Special Biological Resources in Western China, School of Life Sciences, Ningxia University, Yinchuan 750021, ChinaKey Lab of Ministry of Education for Protection and Utilization of Special Biological Resources in Western China, School of Life Sciences, Ningxia University, Yinchuan 750021, ChinaKey Lab of Ministry of Education for Protection and Utilization of Special Biological Resources in Western China, School of Life Sciences, Ningxia University, Yinchuan 750021, ChinaKey Lab of Ministry of Education for Protection and Utilization of Special Biological Resources in Western China, School of Life Sciences, Ningxia University, Yinchuan 750021, China; Corresponding author.Key Lab of Ministry of Education for Protection and Utilization of Special Biological Resources in Western China, School of Life Sciences, Ningxia University, Yinchuan 750021, China; Corresponding author.A growing body of evidence indicates that tumor-associated macrophages (TAMs) are crucial contributors to cancer progression, positioning them as an attractive target for therapeutic intervention. In our previous studies, we found that Platycodon grandiflorum exert anti-melanoma effects by influencing TAMs. Platycodin D (PD), a bioactive compound derived from the dried roots of Platycodon grandiflorum, possesses anti-inflammatory, immunomodulatory, and anti-tumor properties. Based on this, we hypothesized that PD could have anti-melanoma potential and set out to investigate its molecular mechanisms in relation to TAMs. Treatment with PD led to a significant reduction in melanoma tumor weight, inhibition of the mTOR pathway, and suppression of M2-polarized macrophages. PD also downregulated M2 macrophage markers, impaired mitochondrial function, reduced ROS production, and diminished the tumor-promoting functions of TAMs. Through network pharmacology and experimental validation, STAT3 was identified as a central target. PD was shown to decrease JAK2 and p-STAT3 levels, promote JAK2 degradation, and enhance its ubiquitination. In Lyz2cre/cre JAK2flox/flox mice, which lack JAK2 specifically in bone marrow-derived macrophages (BMDMs) were resistant to PD's effects on M2 polarization, mitochondrial function, and melanoma suppression. In summary, PD inhibits melanoma growth by targeting JAK2, which in turn influences M2 polarization and mitochondrial function. This study underscores the potential of PD in regulating TAMs, providing new insights into its potential use in cancer therapy.http://www.sciencedirect.com/science/article/pii/S1756464625000131Platycodin DM2-polarized tumor-associated macrophagesMitochondriaJAK2/STAT3Ubiquitination |
| spellingShingle | Wei Wu Jie Zhang Zijiao Wang Chuan Cheng Dongdong Yuan Li Peng Le Li Platycodin D inhibits tumor proliferation by modulating macrophage polarization through promoting JAK2 ubiquitination Journal of Functional Foods Platycodin D M2-polarized tumor-associated macrophages Mitochondria JAK2/STAT3 Ubiquitination |
| title | Platycodin D inhibits tumor proliferation by modulating macrophage polarization through promoting JAK2 ubiquitination |
| title_full | Platycodin D inhibits tumor proliferation by modulating macrophage polarization through promoting JAK2 ubiquitination |
| title_fullStr | Platycodin D inhibits tumor proliferation by modulating macrophage polarization through promoting JAK2 ubiquitination |
| title_full_unstemmed | Platycodin D inhibits tumor proliferation by modulating macrophage polarization through promoting JAK2 ubiquitination |
| title_short | Platycodin D inhibits tumor proliferation by modulating macrophage polarization through promoting JAK2 ubiquitination |
| title_sort | platycodin d inhibits tumor proliferation by modulating macrophage polarization through promoting jak2 ubiquitination |
| topic | Platycodin D M2-polarized tumor-associated macrophages Mitochondria JAK2/STAT3 Ubiquitination |
| url | http://www.sciencedirect.com/science/article/pii/S1756464625000131 |
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