Stigmasterol sensitizes endometrial cancer cells to chemotherapy by repressing Nrf2 signal pathway
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PRIMARY RESEARCH
Cancer Cell International Open Access
Stigmasterol sensitizes endometrial cancer cells to chemotherapy by repressing Nrf2 signal pathway Hong Liao1,2, Dan Zhu3, Mingzhu Bai4 , Huifen Chen1, Shihuan Yan3, Jing Yu5, Huiting Zhu5, Wenxin Zheng6,7 and Guorong Fan2,8*
Abstract 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. Keywords: Nrf2, Chemoresistance, Hydroxymethylation, Stigmasterol, Endometrial cancer Background Endometrial cancer is the main gynecological malignancy and most of cases occur in post-menopausal women [1–4]. In recent decade, it shows an increasing incidence rate, especially in developing country [3, 5]. Usually, surgery is the optimal therapy strategy for the patients with early-stage endometrial cancer, whereas chemotherapy is chosen to administrate the advanced and recurrent patients. As the first-line chemotherapeutics *Correspondence: [email protected] 2 The Graduate School, Tongji University School of Medicine, Shanghai 200040, China Full list of author information is available at the end of the article
for endometrial cancer therapy, cisplatin and paclitaxel exhibit well-inhibition effect on cancer cell growth, however, chemoresistance is still a major obstacle in endometrial cancer therapy [6]. Therefore, it is urgent to find a biomarker of chemoresistance and develop a new and effective anticancer therapeutic regimen or strategy. As a critical molecule of antioxidant response, Nrf2 has multiple roles in cancer development including chemoresistance, proliferation and anti-apoptosis [7–10]. In previous study, the bad effects of Nrf2 has been addressed, wang et al. demonstrated that high level of Nrf2 enhances chemoresistance, whereas knocki
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