C-Peptide Inhibits Decidualization in Human Endometrial Stromal Cells via GSK3β-PP1

Sana Abdul Khaliq; Mi-Ock Baek; Hye-Jeong Cho; Seung Joo Chon; Mee-Sup Yoon

doi:10.3389/fcell.2020.609551

C-Peptide Inhibits Decidualization in Human Endometrial Stromal Cells via GSK3β-PP1

Front Cell Dev Biol. 2020 Nov 30:8:609551. doi: 10.3389/fcell.2020.609551. eCollection 2020.

Authors

Sana Abdul Khaliq^{1

2

3}, Mi-Ock Baek^{1

2

3}, Hye-Jeong Cho², Seung Joo Chon⁴, Mee-Sup Yoon^{1

2

3}

Affiliations

¹ Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, South Korea.
² Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea.
³ Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, South Korea.
⁴ Department of Obstetrics and Gynecology, Gachon University Gil Medical Center, College of Medicine, Gachon University, Incheon, South Korea.

Abstract

Decidualization refers to the functional differentiation of endometrial stromal cells and plays a significant role in embryo implantation and pregnancy. C-peptide is excreted in equimolar concentrations as that of insulin during the metabolism of proinsulin in pancreatic beta-cells. High levels of C-peptide are correlated with hyperinsulinemia and polycystic ovarian syndrome, which show a defect in decidualization. However, the role of C-peptide in decidualization has not yet been studied. Here, we identified C-peptide as an endogenous antideciduogenic factor. This inhibitory function was confirmed by the reduced expression of decidual markers, including prolactin, insulin-like growth factor-binding protein-1, and Forkhead box protein O1 as well as by the fibroblastic morphological change in the presence of C-peptide. C-peptide also enhanced cellular senescence and decreased the proportion of apoptotic cells during decidualization. In addition, C-peptide potentiated the inhibitory effects of both insulin and palmitic acid in an AKT- and autophagy-independent manner, respectively. Furthermore, C-peptide augmented protein phosphatase 1 (PP1) activity, leading to a reduction in the inhibitory phosphorylation of glycogen synthase kinase (GSK)3β, which resulted in enhanced cellular senescence and decreased apoptosis during decidualization. Taken together, our findings suggest that C-peptide is an antideciduogenic factor acting via the regulation between PP1 and GSK3β in patients with hyperinsulinemia.

Keywords: C-peptide; GSK3 β; PP1; apoptosis; decidualization; senescence.