Diane-35 and Metformin Induce Autophagy and Apoptosis in Polycystic Ovary Syndrome Women with Early-Stage Endometrial Carcinoma.

Yanjun Liu,Xin Li,Yi Feng,Feifei Zhang,Yang Wang,Xing Chen,Dan Yao

doi:10.3390/genes13010131

Abstract

Objective: Women with polycystic ovary syndrome (PCOS) are at increased risk ofendometrial carcinoma (EC). Previous studies indicated that the combined therapy of Diane-35 and metformin significantly suppresses disease progression in PCOS patients with early EC; however, the mechanisms remain unclear. Methods: An established murine model of PCOS with early EC, clinical specimens, and human EC cells was used in this study. The levels of protein and mRNA were measured with Western blotting and RT-PCR, respectively. Cell proliferation was determined with MTT, colony formation, and flow cytometry. Proteins were analyzed with immunofluorescence and immunohistochemistry. Results: Diane-35 and metformin significantly inhibited proliferative activity and promoted apoptosis in EC cells. Additionally, cell autophagy was induced by the combined therapy. Quantitive PCR revealed that Diane-35 and metformin decreased androgen receptor (AR) expression but elevated GLUT4 expression. AR was found to repress GLUT4 expression by binding to the promoter of GLUT4. Moreover, the combined treatment mediated the onset of cellular autophagy by regulating the mTORC pathway via the suppression of IGF-1 and inhibited the development of EC by the activation of the PI3K/mTORC pathway. Conclusion: The results and previous clinical evidence support the use of Diane-35 and metformin combination therapy for patients with PCOS and early EC.

Highlights

Polycystic ovary syndrome (PCOS) is associated with a greater risk of endometrial carcinoma (EC) and is accompanied by elevated levels of androgens, ovulatory arrest, and characteristics of metabolic syndrome, such as insulin resistance and obesity [1,2,3]
The representative image shows that androgen receptor (AR) and IGF-1 staining was increased in the EC patients and was attenuated after the combined treatment with Diane-35 and metformin, but Glucose transporter 4 (GLUT4) had the opposite result (Figure 1A)
The expression of IGF-1 was lower in tissue samples from those patients who underwent an excision operation after treatment with Diane-35 and metformin when compared to EC patients who were not treated (Figure 1B)

Summary

Introduction

Polycystic ovary syndrome (PCOS) is associated with a greater risk of endometrial carcinoma (EC) and is accompanied by elevated levels of androgens, ovulatory arrest, and characteristics of metabolic syndrome, such as insulin resistance and obesity [1,2,3]. The pathophysiology of PCOS is characterized by the abnormal secretion of gonadotropin in response to reduced hypothalamic activity as a consequence of functional changes in the ovaries and insulin dysregulation [4]. Women with PCOS are three times more at risk of EC than women without [8] and more likely to be diagnosed with EC at a later stage [9]. This is a concern, because the survival rate of EC depends on the stage and classification of the disease [10]. Preventative measures include the control of obesity and diabetes; alleviating PCOS may reduce the risk of EC [11,12]

Methods

Results

Discussion

Conclusion