Tankyrase inhibition regulates corpus luteum development and luteal function in gonadotropin‐treated rats

Abstract

Tankyrases are physiological regulators of Axin, a protein involved in several cellular processes, including Wnt signaling. Here, we investigated the effect of a specific Tankyrase inhibitor (XAV939) in follicular-luteal dynamics, and its possible relationship with ovarian vascular development. Studies were designed to analyze the effect of intrabursa administration of XAV939 in gonadotropin-treated prepubertal rats. In particular, we examined follicle and corpus luteum development, steroidogenesis, angiogenic markers, and apoptotic parameters. We found that in vivo inhibition of Wnt signaling impaired corpus luteum development, with a decrease in the number of corpora lutea balanced by a high number of cysts; decreased circulating progesterone levels, likely due to a decrease in Steroidogenic acute regulatory protein content in the corpus luteum; and increased pro-apoptotic parameters. In addition, Extracellular signal-regulated kinase phosphorylation, Vascular endothelium growth factor 120 content, and endothelial cell area were diminished in corpora lutea of inhibitor-treated ovaries. Thus, Wnt/β-catenin signaling appears to participate in the regulation of corpus luteum development and luteal cell function.

Convergence of Wnt and Notch signaling controls ovarian cancer cell survival

“…In breast cancer cells, XAV939 has also been observed to inhibit cell growth, and, in concordance with our findings in rat corpus luteum, to increase Axin protein levels (the limiting factor of the β‐catenin destruction complex) and to decrease Wnt‐induced transcriptional activity (Accialini et al, ; Bao et al, ). Regarding ICG‐001, the only study performed in ovarian cancer cells showed that ovarian cancer initiating cells treated with ICG‐001 are more sensitive to cisplatin, and that this inhibitor also decreases stem cell frequency in platinum‐resistance cells (Nagaraj et al, ).…”

Updates on molecular and environmental determinants of luteal progesterone production

“…Accialini et al demonstrated that in vivo ovarian inhibition of the Wnt signaling pathway via intrabursal injections of small molecule inhibitors resulted in impaired corpus luteum development, decreased STAR and circulating progesterone. Notably, this work also linked Wnt signaling to the critical process of luteal angiogenesis by demonstrating decreased expression of ovarian VEGF isoforms after Wnt pathway inhibition 27 . Moreover, as further evidence of crosstalk between these important pathways, inhibition of Wnt/β-catenin in vitro in cultured rat corpora lutea stimulated Notch signaling (via an increase in HES expression), suggesting a mechanism by which interactions between the critical Notch and Wnt pathways can promote progesterone signaling 28 .…”