Using β-Elemene to reduce stemness and drug resistance in osteosarcoma: A focus on the AKT/FOXO1 signaling pathway and immune modulation
Objective: Osteosarcoma, a highly malignant bone tumor, poses significant treatment challenges due to its propensity for stemness and drug resistance, particularly against doxorubicin (DOX). This study aims to investigate the mechanism by which β-elemene reduces the stemness of osteosarcoma stem cel...
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| Language: | English |
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Elsevier
2025-02-01
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| Series: | Journal of Bone Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212137424001350 |
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| author | Shaochun Zhang Zhijie Xing Jing Ke |
| author_facet | Shaochun Zhang Zhijie Xing Jing Ke |
| author_sort | Shaochun Zhang |
| collection | DOAJ |
| description | Objective: Osteosarcoma, a highly malignant bone tumor, poses significant treatment challenges due to its propensity for stemness and drug resistance, particularly against doxorubicin (DOX). This study aims to investigate the mechanism by which β-elemene reduces the stemness of osteosarcoma stem cells and ultimately decreases DOX resistance by inhibiting the Akt/FoxO1 signaling pathway and activating a macrophage-mediated inflammatory microenvironment. Methods: Osteosarcoma stem cells were isolated and induced for DOX resistance. In vitro and in vivo models were employed to assess β-elemene’s impact on cell viability, stemness, and drug resistance. Bioinformatics analysis, flow cytometry, and immunofluorescence staining were used to evaluate signaling pathway activity and macrophage polarization. Additionally, an osteosarcoma xenograft mouse model was established to confirm the therapeutic effects of β-elemene. Results: In vivo animal experiments demonstrated that β-elemene reduces osteosarcoma resistance. Bioinformatics analysis revealed that AKT1 is a key core gene in osteosarcoma progression, acting through the FOXO signaling pathway. Additionally, AKT inhibits immune cell infiltration in osteosarcoma and suppresses immune responses during osteosarcoma progression. β-elemene may influence osteosarcoma progression by mediating TP53 to regulate PTEN and subsequently AKT1. In vitro experiments showed that β-elemene promotes M1 macrophage activation by inhibiting the Akt/FoxO1 signaling axis, thereby reducing the stemness of osteosarcoma stem cells. Finally, in vivo animal experiments confirmed that β-elemene reduces osteosarcoma resistance by promoting M1 macrophage activation through inhibition of the Akt/FoxO1 signaling axis. Conclusion: β-Elemene demonstrates promising potential in reducing osteosarcoma stemness and drug resistance via dual mechanisms: targeting the AKT/FOXO1 pathway and modulating the tumor immune microenvironment. These findings suggest β-elemene as a potential adjunct therapy for osteosarcoma, providing novel therapeutic strategies to overcome chemotherapy resistance and improve patient outcomes. |
| format | Article |
| id | doaj-art-cdfaa6f310d84e8b9c007fe472570633 |
| institution | Kabale University |
| issn | 2212-1374 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Bone Oncology |
| spelling | doaj-art-cdfaa6f310d84e8b9c007fe4725706332025-01-20T04:17:25ZengElsevierJournal of Bone Oncology2212-13742025-02-0150100655Using β-Elemene to reduce stemness and drug resistance in osteosarcoma: A focus on the AKT/FOXO1 signaling pathway and immune modulationShaochun Zhang0Zhijie Xing1Jing Ke2Orthopedics Department, The Central Hospital of Ezhou, Ezhou 436000, China; Corresponding author at: Orthopedics Department, The Central Hospital of Ezhou, No.9 Wenxing Road, Echeng District, Ezhou 436000, Hubei Province, China.Orthopedics Department, The Central Hospital of Ezhou, Ezhou 436000, ChinaDepartment of Endocrinology, The Central Hospital of Ezhou, Ezhou 436000, ChinaObjective: Osteosarcoma, a highly malignant bone tumor, poses significant treatment challenges due to its propensity for stemness and drug resistance, particularly against doxorubicin (DOX). This study aims to investigate the mechanism by which β-elemene reduces the stemness of osteosarcoma stem cells and ultimately decreases DOX resistance by inhibiting the Akt/FoxO1 signaling pathway and activating a macrophage-mediated inflammatory microenvironment. Methods: Osteosarcoma stem cells were isolated and induced for DOX resistance. In vitro and in vivo models were employed to assess β-elemene’s impact on cell viability, stemness, and drug resistance. Bioinformatics analysis, flow cytometry, and immunofluorescence staining were used to evaluate signaling pathway activity and macrophage polarization. Additionally, an osteosarcoma xenograft mouse model was established to confirm the therapeutic effects of β-elemene. Results: In vivo animal experiments demonstrated that β-elemene reduces osteosarcoma resistance. Bioinformatics analysis revealed that AKT1 is a key core gene in osteosarcoma progression, acting through the FOXO signaling pathway. Additionally, AKT inhibits immune cell infiltration in osteosarcoma and suppresses immune responses during osteosarcoma progression. β-elemene may influence osteosarcoma progression by mediating TP53 to regulate PTEN and subsequently AKT1. In vitro experiments showed that β-elemene promotes M1 macrophage activation by inhibiting the Akt/FoxO1 signaling axis, thereby reducing the stemness of osteosarcoma stem cells. Finally, in vivo animal experiments confirmed that β-elemene reduces osteosarcoma resistance by promoting M1 macrophage activation through inhibition of the Akt/FoxO1 signaling axis. Conclusion: β-Elemene demonstrates promising potential in reducing osteosarcoma stemness and drug resistance via dual mechanisms: targeting the AKT/FOXO1 pathway and modulating the tumor immune microenvironment. These findings suggest β-elemene as a potential adjunct therapy for osteosarcoma, providing novel therapeutic strategies to overcome chemotherapy resistance and improve patient outcomes.http://www.sciencedirect.com/science/article/pii/S2212137424001350β-ElemeneOsteosarcomaDrug ResistanceProtein Kinase B/Forkhead Box O1 Signaling PathwayM1 Type Macrophages |
| spellingShingle | Shaochun Zhang Zhijie Xing Jing Ke Using β-Elemene to reduce stemness and drug resistance in osteosarcoma: A focus on the AKT/FOXO1 signaling pathway and immune modulation Journal of Bone Oncology β-Elemene Osteosarcoma Drug Resistance Protein Kinase B/Forkhead Box O1 Signaling Pathway M1 Type Macrophages |
| title | Using β-Elemene to reduce stemness and drug resistance in osteosarcoma: A focus on the AKT/FOXO1 signaling pathway and immune modulation |
| title_full | Using β-Elemene to reduce stemness and drug resistance in osteosarcoma: A focus on the AKT/FOXO1 signaling pathway and immune modulation |
| title_fullStr | Using β-Elemene to reduce stemness and drug resistance in osteosarcoma: A focus on the AKT/FOXO1 signaling pathway and immune modulation |
| title_full_unstemmed | Using β-Elemene to reduce stemness and drug resistance in osteosarcoma: A focus on the AKT/FOXO1 signaling pathway and immune modulation |
| title_short | Using β-Elemene to reduce stemness and drug resistance in osteosarcoma: A focus on the AKT/FOXO1 signaling pathway and immune modulation |
| title_sort | using β elemene to reduce stemness and drug resistance in osteosarcoma a focus on the akt foxo1 signaling pathway and immune modulation |
| topic | β-Elemene Osteosarcoma Drug Resistance Protein Kinase B/Forkhead Box O1 Signaling Pathway M1 Type Macrophages |
| url | http://www.sciencedirect.com/science/article/pii/S2212137424001350 |
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