Bidirectional Interaction Between Unfolded-Protein-Response Key Protein HSPA5 and Estrogen Signaling in Human Endometrium1

Abstract

The human endometrium is a dynamic tissue that undergoes cyclic changes under the influence of steroid hormones as well as numerous local paracrine and autocrine factors. Heat shock 70 kDa protein (HSPA5; also known as GRP78/BiP), a molecular chaperone within the endoplasmic reticulum, plays crucial roles in normal cellular processes as well as in stress conditions, in which it is a central regulator for the unfolded protein response (UPR). We hypothesized that HSPA5 expression level is variable throughout the menstrual cycle in human endometrium and that estrogen signaling cross-talks with UPR signaling by interacting with HSPA5. HSPA5 expression throughout the menstrual cycle was evaluated in vivo in normal human endometrium. Using in vitro techniques, we then assessed the bidirectional regulation of HSPA5 and estrogen signaling in human endometrial glandular (Ishikawa) and stromal cells (ESC). HSPA5 immunoreactivity in endometrial glandular and stromal cells was cycle-dependent, and was significantly higher in phases of the menstrual cycle when estradiol (E(2)) levels are known to be the lowest compared with the rest of the cycle (P < 0.001). E(2) did not affect HSPA5 expression after 8-24 h incubation in Ishikawa cells and ESC in vitro. However, tunicamycin-induced HSPA5 expression was significantly lowered in these cells when pretreated with E(2) (P < 0.01 and P < 0.05, respectively). On the other hand, tunicamycin decreased E(2) up-regulated alkaline phosphatase activity (P < 0.001). In conclusion, there is cycle-dependent HSPA5 expression with a possible inverse correlation between HSPA5 expression and E(2) levels in human endometrium. We suggest that estrogen signaling cross-talks with the UPR cascade by interacting with HSPA5, as supported by our in vitro findings.

The endoplasmic reticulum stress marker, glucose-regulated protein-78 (GRP78) in visceral adipocytes predicts endometrial cancer progression and patient survival

“…Furthermore, we also demonstrated that histologically normal endometrium can variably express GRP78, a finding that is consistent with previously reports [36]. To determine whether or not estrogen plays a direct effect on ER stress in human EC cells, Guzel and colleagues directly applied estradiol to Ishikawa cells, and showed no GRP78 induction [37]. In fact, pre-treatment of both Ishikawa cells and primary endometrial stromal cells appeared to abrogate chemically-induced ER stress, further supporting that estrogen exposure may not directly increase endometrial ER stress [37].…”

Regulatory T cells, inflammation, and endoplasmic reticulum stress in women with defective endometrial receptivity

“…Furthermore, HSPA5 protein expression was up-regulated in the midsecretory endometrial tissues of both RM and RIF patients. This is particularly relevant because it has been recently described that HSPA5 expression fluctuates in the normal endometrium during the menstrual cycle, with the lowest degree of expression in the midsecretory phase (43). Thus, deregulated HSPA5 expression might play a role in defective implantation.…”

Endoplasmic Reticulum (ER) Stress and Hypoxia Response Pathways Interact to Potentiate Hypoxia-inducible Factor 1 (HIF-1) Transcriptional Activity on Targets Like Vascular Endothelial Growth Factor (VEGF)

“…This can occur in normal developmental and physiological contexts, like establishing the vasculature of a placenta (29) and promoting wound healing (30,31), as well as pathological conditions, like increasing tumor vascularization (10,32). Although a large number of studies exist to demonstrate activation of both pathways in these various tissues and conditions, nearly all of them study the pathways independently, and, thus, very little is known about possible interactions between these pathways on shared transcriptional targets like VEGF.…”