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HTB50-2 Inhibits Growth and Migration of Triple-negative Breast Cancer via FOSL2/FOXC1 Signaling Axis and Subsequent
Na Liu1, Wen-Ying Yin1, Wen-Qi Duan1
1School of Biological Science and Technology, University of Jinan, Jinan, 250022, China.
Background:
The manipulation of ferroptosis in cancer cells is a possible therapeutic technique that has been investigated for use in the treatment of cancer. Consequently, ferroptosis-inducing medications have recently received increased interest in cancer therapy. In this research, we assessed the anticancer efficacy of 14β-hydroxy- 3β-(β-D-Glucopyranosyloxy)-5α-bufa-20,22-dienolide (HTB50-2), a natural product derived from the plant Helleborus thibetanus Franch, in Triple-Negative Breast Cancer (TNBC). Moreover, we also studied its potential mechanisms.
Methods:
The biological effects of HTB50-2 in a series of breast cancer cell lines were analyzed using sulforhodamine B (SRB) and other methods. The migration ability was analyzed using three methods: wound healing assay, transwell assay, and Western blot. Meanwhile, the potential therapeutic value of HTB50-2 was evaluated in BALB/c mice by orthotopic transplantation. Transcriptome sequencing was conducted to explore the FOS-like antigen 2 (FOSL2) gene, and its role in ferroptosis was verified by Western blot and immunohistochemistry. The association of FOSL2 and ferroptosis-related genes was analyzed using NetworkAnalyst databases, and a TF-Gene interaction network was constructed.
Results:
Ferroptosis was found to be induced in TNBC cells by HTB50-2. Furthermore, HTB50-2 inhibited tumor development by inducing ferroptosis in TNBC in vivo. Mechanistically, we demonstrated that a transcription factor FOSL2 mediated ferroptosis by HTB50-2. Additionally, it was found that Forkhead box C1 (FOXC1) was regulated by FOSL2 and correlated with ferroptosis.
Conclusion:
Our data suggest that HTB50-2 exerts its anti-cancer properties by ferroptosis via FOSL2/FOXC1 signaling pathway. Hence, HTB50-2 has an important application potential in the treatment of TNBC.
Insights
14β-hydroxy-3β-(β-D-Glucopyranosyloxy)-5α-bufa-20,22-dienolide (HTB50-2) induces ferroptosis in Triple-Negative Breast Cancer (TNBC) cells, inhibiting tumor growth. This natural compound targets the FOSL2/FOXC1 signaling pathway for potential TNBC therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Ferroptosis induction is a promising cancer therapy strategy.
- Natural products are gaining interest for cancer treatment.
- Triple-Negative Breast Cancer (TNBC) remains a therapeutic challenge.
Purpose of the Study:
- To evaluate the anticancer efficacy of HTB50-2 in TNBC.
- To elucidate the underlying mechanisms of HTB50-2's action.
- To explore the role of FOSL2 and FOXC1 in HTB50-2-mediated ferroptosis.
Main Methods:
- Sulforhodamine B assay and cell migration assays (wound healing, transwell).
- In vivo studies using orthotopic transplantation in BALB/c mice.
- Transcriptome sequencing, Western blot, and immunohistochemistry to analyze FOSL2 and FOXC1.
Main Results:
- HTB50-2 effectively induced ferroptosis in TNBC cells.
- HTB50-2 inhibited tumor growth in vivo by promoting ferroptosis.
- FOSL2 was identified as a key mediator of HTB50-2-induced ferroptosis, regulating FOXC1.
Conclusions:
- HTB50-2 exhibits anti-cancer properties in TNBC through ferroptosis induction.
- The FOSL2/FOXC1 signaling pathway is crucial for HTB50-2's therapeutic effect.
- HTB50-2 demonstrates significant potential for TNBC treatment.
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