HB-EGF induces mitochondrial dysfunction via estrogen hypersecretion in granulosa cells dependent on cAMP-PKA-JNK/ERK-Ca²⁺-FOXO1 pathway

Abstract

Polycystic ovarian syndrome (PCOS) is one of the most prevalent endocrinopathies and the leading cause of anovulatory infertility, but its pathogenesis remains elusive. Although HB-EGF is involved in ovarian cancer progression, there is still no clarity about its relevance with PCOS. The present study exhibited that abundant HB-EGF was noted in follicular fluid from PCOS women, where it might induce the granulosa cells (GCs) production of more estrogen via the elevation of CYP19A1 expression after binding to EGFR. Furthermore, HB-EGF transduced intracellular downstream cAMP-PKA signaling to promote the phosphorylation of JNK and ERK whose blockage impeded the induction of HB-EGF on estrogen secretion. Meanwhile, HB-EGF enhanced the accumulation of intracellular Ca 2+ whose chelation by BAPTA-AM abrogated the stimulation of HB-EGF on FOXO1 along with an obvious diminishment for estrogen production. cAMP-PKA-JNK/ERK-Ca 2+ pathway played an important role in the crosstalk between HB-EGF and FOXO1. Treatment of GCs with HB-EGF resulted in mitochondrial dysfunction as evinced by the reduction of ATP content, mtDNA copy number and mitochondrial membrane potential. Additionally, HB-EGF facilitated the opening of mitochondrial permeability transition pore via targeting BAX and raised the release of cytochrome C from mitochondria into the cytosol to trigger the apoptosis of GCs, but this effectiveness was counteracted by estrogen receptor antagonist. Collectively, HB-EGF might induce mitochondrial dysfunction and GCs apoptosis through advancing estrogen hypersecretion dependent on cAMP-PKA-JNK/ERK-Ca 2+ -FOXO1 pathway and act as a promising therapeutic target for PCOS.

HB-EGF upregulates StAR expression and stimulates progesterone production through ERK1/2 signaling in human granulosa-lutein cells

“…In patients without implantation, the follicular fluid HB-EGF levels are 230 pg/mL [30]. However, a recent study shows that the follicular fluid HB-EGF levels in IVF patients without polycystic ovarian syndrome (PCOS) are around 3 ng/ mL, which is 10-fold higher than the value reported by the study mentioned above [31]. Therefore, future studies will need to confirm the protein levels of HB-EGF in human follicular fluid.…”

LDHA deficiency inhibits trophoblast proliferation via the PI3K/AKT/FOXO1/CyclinD1 signaling pathway in unexplained recurrent spontaneous abortion

“…LDHA overexpression led to a reduction of cells in the G0/G1 phase, while MK‐2206 eliminated this effect, arresting cells in the G0/G1 phase (Figure 5D,E). To further examine the effect of FOXO1 on trophoblast proliferation, we treated HTR‐8 cells with 10 μM of FOXO1 inhibitor AS1842856 for 24 h. The AS1842856 could inhibit the activity of FOXO1 by binding with it 23–25 . As the FOXO1 activity was inhibited, more HTR‐8 cells entered the S phase from the G0/G1 phase (Figure S3A,B) and expressed higher CyclinD1 (Figure S3C,D).…”

“…To further examine the effect of FOXO1 on trophoblast proliferation, we treated HTR-8 cells with 10 μM of FOXO1 inhibitor AS1842856 for 24 h. The AS1842856 could inhibit the activity of FOXO1 by binding with it. [23][24][25] As the FOXO1 activity was inhibited, more HTR-8 cells entered the S phase from the G0/G1 phase (Figure S3A,B) and expressed higher CyclinD1 (Figure S3C,D). Together, these findings in vitro suggest that LDHA regulates the trophoblast cell cycle via the PI3K/AKT/FOXO1 pathway, and the effect was related to Cyclin D1 and CDK4 protein modulation.…”

The interplay between androgens and the immune response in polycystic ovary syndrome

“…A recent study showed that copious amounts of HB-EGF are present in the follicular fluid in PCOS. It is suggested that the presence of abundant HB-EGF in the fluid may bring about estrogen hypersecretion through the JNK/ERK pathway, resulting in apoptosis of granulosa cells and mitochondrial dysfunction [ 65 ]. As estrogen is considered to be an androgen, the influence of HB-EGF on the JNK/ERK pathway may be another contributor to hyperandrogenism in PCOS.…”