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Icaritin inhibits endometrial carcinoma cells by suppressing O-GlcNAcylation of FOXC1
Yufei Wang1, Gang Wang2, Yingping Liu2
1Institute of Neurology, General Hospital of Shenyang Military Command, Shenyang, Liaoning 110016, China.
Background:
Icaritin has a wide range of pharmacological activities, including significant an-titumor activity. However, the mechanism of action of icaritin in endometrial cancer (UCEC) remains unknown. FOX proteins are a highly conserved transcription factor superfamily that play important roles in epithelial cell differentiation, tumor metastasis, angiogenesis, and cell cycle regulation. FOXC1 is an important member of the FOX protein family. FOXC1 is aberrantly expressed in endometrial cancer and may play a role in the migration and invasion of endometrial cancer; however, its mechanism of action has not yet been reported. O-GlcNAc glycosylation is a common post-translational modification. In endometrial cancer, high levels of O-GlcNAcylation promote cell proliferation, migration, and invasion. Cancer development is often accompanied by O-GlcNAc modification of proteins; however, O-GlcNAc modification of the transcription factor FOXC1 has not been reported to date.
Purpose:
To investigate the inhibitory effects of icaritin on RL95-2 and Ishikawa endometrial cancer cells in vitro and in vivo and to elucidate the possible molecular mechanisms.
Methods/Study Design:
CCK8, colony formation, migration, and invasion assays were used to determine the inhibitory effects of icaritin on endometrial cancer cells in vitro. Cell cycle regulation was assayed by flow cytometry. Protein levels were measured based on western blotting. The level of FOXC1 expression in endometrial cancer tissues was determined by immunohistochemistry. To assess whether icaritin also has activity in vivo, its effect on tumor xenografts was evaluated.
Results:
Immunohistochemical analysis of clinical samples revealed that FOXC1 expression was significantly higher in endometrial cancer tissues than in normal tissues. Downregulation of FOXC1 inhibited the proliferative, colony formation, migration, and invasive abilities of RL95-2 and Ishikawa endometrial cancer cells. Icaritin inhibited the proliferation, colony formation, migration, and invasion of endometrial cancer cells and blocked the cell cycle in S phase. Icaritin affected O-GlcNAc modification of FOXC1 and thus the stability of FOXC1, which subsequently triggered the inhibition of endometrial cancer cell proliferation.
Conclusion:
The anti-endometrial cancer effect of icaritin is related to the inhibition of abnormal O-GlcNAc modification of FOXC1, which may provide an important theoretical foundation for the use of icaritin against endometrial cancer.
Insights
Icaritin inhibits endometrial cancer growth by targeting FOXC1 O-GlcNAc modification. This study reveals a novel mechanism for icaritin
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Icaritin exhibits anti-tumor properties, but its mechanism in endometrial cancer (UCEC) is unclear.
- FOXC1, a transcription factor, is overexpressed in UCEC and linked to cancer cell migration and invasion.
- O-GlcNAcylation, a post-translational modification, is elevated in UCEC and promotes cancer progression, but its role with FOXC1 is unknown.
Purpose of the Study:
- To investigate icaritin's inhibitory effects on endometrial cancer cells (RL95-2 and Ishikawa) in vitro and in vivo.
- To elucidate the molecular mechanisms underlying icaritin's action, focusing on FOXC1 and O-GlcNAcylation.
Main Methods:
- Cell proliferation, colony formation, migration, and invasion assays were performed.
- Cell cycle analysis was conducted using flow cytometry.
- Western blotting assessed protein levels, and immunohistochemistry evaluated FOXC1 expression in clinical samples. In vivo efficacy was tested using tumor xenografts.
Main Results:
- FOXC1 expression was significantly higher in endometrial cancer tissues compared to normal tissues.
- Downregulating FOXC1 reduced proliferation, colony formation, migration, and invasion in endometrial cancer cells.
- Icaritin inhibited cancer cell proliferation, colony formation, migration, and invasion, arresting the cell cycle in S phase, and altered FOXC1 O-GlcNAc modification and stability.
Conclusions:
- Icaritin's anti-endometrial cancer effects are linked to inhibiting aberrant O-GlcNAc modification of FOXC1.
- This finding provides a theoretical basis for using icaritin as a potential therapeutic agent for endometrial cancer.
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