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Original Article
Synergistic Activation of LEPR and ADRB2 Induced by Leptin Enhances ROS Generation in TNBC Cells
Chang Liu1orcid , Jing Yu1, Yongjun Du1, Yu Xie1, Xiaofei Song1, Chang Liu1, Yan Yan2, Yue Wang1,2orcid , Junfang Qin1orcid

DOI: https://doi.org/10.4143/crt.2024.368 [Accepted]
Published online: August 21, 2024
1School of Medicine, Nankai University, Tianjin, China
2Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, Hospital of Stomatology, Nankai University, Tianjin, China
Corresponding author:  Yue WangEmail: wangyue@nankai.edu.cn
Junfang QinEmail: qjf@nankai.edu.cn
Received: 15 April 2024   • Accepted: 19 August 2024
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Purpose
Leptin interacts not only with leptin receptor (LEPR) but also engages with other receptors. While the pro-oncogenic effects of the adrenergic receptor β2 (ADRB2) are well-established, the role of leptin in activating ADRB2 in triple-negative breast cancer (TNBC) remains unclear.
Materials and Methods
The pro-carcinogenic effects of LEPR were investigated using murine TNBC cell lines, 4T1 and EMT6, and a tumor-bearing mouse model. Expression levels of LEPR, NOX4, and ADRB2 in TNBC cells and tumor tissues were analyzed via Western blot and qPCR. Changes in reactive oxygen species (ROS) levels were assessed using flow cytometry and MitoSox staining, while immunofluorescence double-staining confirmed the co-localization of LEPR and ADRB2.
Results
LEPR activation promoted NOX4-derived ROS and mitochondrial ROS production, facilitating TNBC cell proliferation and migration, effects which were mitigated by the LEPR inhibitor Allo-aca. Co-expression of LEPR and ADRB2 was observed on cell membranes, and bioinformatics data revealed a positive correlation between the two receptors. Leptin activated both LEPR and ADRB2, enhancing intracellular ROS generation and promoting tumor progression, which was effectively countered by a specific ADRB2 inhibitor ICI118551. In vivo, leptin injection accelerated tumor growth and lung metastases without affecting appetite, while treatments with Allo-aca or ICI118551 mitigated these effects.
Conclusion
This study demonstrates that leptin stimulates the growth and metastasis of TNBC through the activation of both LEPR and ADRB2, resulting in increased ROS production. These findings highlight LEPR and ADRB2 as potential biomarkers and therapeutic targets in TNBC.


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