Int J Biol Sci 2019; 15(3):714-725. doi:10.7150/ijbs.31425

Research Paper

Differential Expression Patterns of Glycolytic Enzymes and Mitochondria-Dependent Apoptosis in PCOS Patients with Endometrial Hyperplasia, an Early Hallmark of Endometrial Cancer, In Vivo and the Impact of Metformin In Vitro

Tao Wang1,2*, Jiao Zhang3*, Min Hu4,5,6, Yuehui Zhang2,4, Peng Cui4, Xin Li4,7,8, Juan Li4,5, Edvin Vestin1, Mats Brännström9, Linus R Shao4✉, Håkan Billig4

1. The School of Basic Medical Science, Heilongjiang University of Chinese Medicine, 150040 Harbin, China
2. Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040 Harbin, China
3. Department of Acupuncture and Moxibustion, Second Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040 Harbin, China
4. Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden
5. Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, 510120 Guangzhou, China
6. Institute of Integrated Traditional Chinese Medicine and Western Medicine, Guangzhou Medical University, 510120 Guangzhou, China
7. Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 200011 Shanghai, China
8. Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 200011 Shanghai, China
9. Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Gothenburg, 41345 Gothenburg, Sweden
*These authors should be regarded as joint first authors

Abstract

The underlying mechanisms of polycystic ovarian syndrome (PCOS)-induced endometrial dysfunction are not fully understood, and although accumulating evidence shows that the use of metformin has beneficial effects in PCOS patients, the precise regulatory mechanisms of metformin on endometrial function under PCOS conditions have only been partially explored. To address these clinical challenges, this study aimed to assess the protein expression patterns of glycolytic enzymes, estrogen receptor (ER), and androgen receptor (AR) along with differences in mitochondria-dependent apoptosis in PCOS patients with and without endometrial hyperplasia in vivo and to investigate the effects of metformin in PCOS patients with endometrial hyperplasia in vitro. Here, we showed that compared to non-PCOS patients and PCOS patients without hyperplasia, the endometria from PCOS patients with hyperplasia had a distinct protein expression pattern of glycolytic enzymes, including pyruvate kinase isozyme M2 isoform (PKM2) and pyruvate dehydrogenase (PDH), and mitochondrial transcription factor A (TFAM). In PCOS patients with endometrial hyperplasia, increased glandular epithelial cell secretion and infiltrated stromal cells in the glands were associated with decreased PDH immunoreactivity in the epithelial cells. Using endometrial tissues from PCOS patients with hyperplasia, we found that in response to metformin treatment in vitro, hexokinase 2 (HK2) expression was decreased, whereas phosphofructokinase (PFK), PKM2, and lactate dehydrogenase A (LDHA) expression was increased compared to controls. Although there was no change in PDH expression, metformin treatment increased the expression of TFAM and cleaved caspase-3. Moreover, our in vivo study showed that while endometrial ERβ expression was no different between non-PCOS and PCOS patients regardless of whether or not hyperplasia was present, ERα and AR protein expression was gradually increased in women with PCOS following the onset of endometrial hyperplasia. Our in vitro study showed that treatment with metformin inhibited ERα expression without affecting ERβ expression. Our findings suggest that decreased glycolysis and increased mitochondrial activity might contribute to the onset of ERα-dependent endometrial hyperplasia and that metformin might directly reverse impaired glycolysis and normalize mitochondrial function in PCOS patients with endometrial hyperplasia.

Keywords: glycolysis, mitochondria, apoptosis, endometrial hyperplasia, metformin, PCOS

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How to cite this article:
Wang T, Zhang J, Hu M, Zhang Y, Cui P, Li X, Li J, Vestin E, Brännström M, Shao LR, Billig H. Differential Expression Patterns of Glycolytic Enzymes and Mitochondria-Dependent Apoptosis in PCOS Patients with Endometrial Hyperplasia, an Early Hallmark of Endometrial Cancer, In Vivo and the Impact of Metformin In Vitro. Int J Biol Sci 2019; 15(3):714-725. doi:10.7150/ijbs.31425. Available from http://www.ijbs.com/v15p0714.htm