Work

Using β-Elemene to reduce stemness and drug resistance in osteosarcoma: A focus on the AKT/FOXO1 signaling pathway and immune modulation

Year: 2024

Type: article

Abstract: • First report: β-elemene activates M1 macrophage inflammation via AKTFOXO1 in osteosarcoma. • β-elemene targets osteosarcoma stem cells,suppressing their stemness. • β-elemene enhances osteosarcoma sensitivity to DOX chemotherapy. • AKT1 identified as osteosarcoma progression key gene by bioinformatics. • New targets and strategies for osteosarcoma treatment uncovered. 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. 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. 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. 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.

Source: Journal of bone oncology

DOI: 10.1016/j.jbo.2024.100655

Authors: Shaochun Zhang, Zhijie Xing, Jing Ke

Institution: Ezhou Central Hospital

Language: English

Topic: Sarcoma Diagnosis and Treatment

Subfield: Pulmonary and Respiratory Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,720