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Stigmasterol sensitizes endometrial cancer cells to chemotherapy by repressing Nrf2 signal pathway
Hong Liao1,2, Dan Zhu3, Mingzhu Bai4
1Department of Clinical Laboratory Medicine, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, 200040 China.
Background:
Chemoresistance reduces the 5-year survival rate of endometrial cancer patient, which is the current major obstacle for cancer therapy. Increasing evidence state that Nrf2 contributes to chemoresistance in several kinds of cancer. However, its role in endometrial cancer cells remains unclarified.
Methods:
Immunohistochemistry staining was used to detect the expression of Nrf2 in normal patient and endometrial cancer patient. Stable transfection Ishikawa cell line with high level of Nrf2 was established to evaluate its role in chemoresistance. Dot blot assays were used to assess global hydroxymethylation level after stigmasterol treatment. Cellular growth profile was detected by CCK8 assay. Western blot was used to evaluate the changes of the target molecules after various treatments.
Results:
Nrf2 is overexpressed in endometrial cancer tissues compared with the normal endometrium. Overexpression of Nrf2 resulted in decrease sensitivity to cisplatin. In addition, stigmasterol has been identified as a novel Nrf2 inhibitor. It enhanced the sensitivity of endometrial cancer cells to cisplatin, and the underlying mechanism is that stigmasterol declines the Nrf2 protein level.
Conclusions:
Our findings identified stigmasterol as a new potential inhibitor of Nrf2 and highlight a critical role of stigmasterol in overcoming chemoresistance in endometrial cancer therapy.
Insights
Stigmasterol inhibits Nrf2, enhancing chemotherapy effectiveness in endometrial cancer. This discovery offers a new strategy to overcome chemoresistance and improve patient survival rates.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Chemoresistance significantly lowers endometrial cancer patient survival.
- Nuclear factor erythroid 2-related factor 2 (Nrf2) is implicated in chemoresistance across various cancers.
- The specific role of Nrf2 in endometrial cancer chemoresistance requires clarification.
Purpose of the Study:
- To investigate the role of Nrf2 in endometrial cancer chemoresistance.
- To identify potential therapeutic agents that can overcome Nrf2-mediated chemoresistance.
Main Methods:
- Immunohistochemistry to assess Nrf2 expression in endometrial tissues.
- Cell line models to evaluate Nrf2's impact on chemoresistance.
- CCK8 and Western blot assays to analyze cellular responses and molecular changes.
- Dot blot assays to measure hydroxymethylation levels.
Main Results:
- Nrf2 is overexpressed in endometrial cancer tissues.
- Elevated Nrf2 levels decrease sensitivity to cisplatin chemotherapy.
- Stigmasterol acts as an Nrf2 inhibitor, reducing Nrf2 protein levels.
- Stigmasterol treatment restores sensitivity to cisplatin in endometrial cancer cells.
Conclusions:
- Stigmasterol is identified as a novel inhibitor of Nrf2.
- Stigmasterol demonstrates potential in overcoming chemoresistance in endometrial cancer therapy.
- Targeting Nrf2 with stigmasterol represents a promising therapeutic strategy for endometrial cancer.
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