Inhibitory effect of 2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo(b)pyran (K-1) on human primary endometrial hyperplasial cells mediated via combined suppression of Wnt/β-catenin signaling and PI3K/Akt survival pathway

Abstract

Endometrial hyperplasia is a precursor to the most common gynecologic cancer diagnosed in women. Apart from estrogenic induction, aberrant activation of the Wnt/β-catenin signal is well known to correlate with endometrial hyperplasia and its carcinoma. The benzopyran compound 2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo (b) pyran(K-1), a potent antiestrogenic agent, has been shown to have apoptosis-inducing activity in rat uterine hyperplasia. The current study was undertaken to explore the effect of the benzopyran compound K-1 on growth and Wnt signaling in human endometrial hyperplasial cells. Primary culture of atypical endometrial hyperplasial cells was characterized by the epithelial cell marker cytokeratin-7. Results revealed that compound K-1 reduced the viability of primary endometrial hyperplasial cells and expression of ERα, PR, PCNA, Wnt7a, FZD6, pGsk3β and β-catenin without affecting the growth of the primary culture of normal endometrial cells. The β-catenin target genes CyclinD1 and c-myc were also found to be reduced, whereas the expression of axin2 and Wnt/β-catenin signaling inhibitor Dkk-1 was found to be upregulated, which caused the reduced interaction of Wnt7a and FZD6. Nuclear accumulation of β-catenin was found to be decreased by compound K-1. K-1 also suppressed the pPI3K/pAkt survival pathway and induced the cleavage of caspases and PARP, thus subsequently causing the apoptosis of endometrial hyperplasial cells. In conclusion, compound K-1 suppressed the growth of human primary endometrial hyperplasial cells through discontinued Wnt/β-catenin signaling and induced apoptosis via inhibiting the PI3K/Akt survival pathway.

Inhibition of the Tcf/beta-catenin complex increases apoptosis and impairs adrenocortical tumor cell proliferation and adrenal steroidogenesis

“…We also observed that PNU led to increased mRNA expression of the beta-catenin target genes CCND1 and AXIN2 . In agreement, it has been shown that the Wnt/beta-catenin pathway inhibition resulted in increased AXIN2 mRNA expression in endometrial cells [ 31 ]. Furthermore, our data suggest a potential effect on beta-catenin-dependent transcription, a mechanism of action that has been reported for other inhibitors of the Tcf/beta-catenin complex [ 18 , 32 ].…”

FOXP1 forkhead transcription factor is associated with the pathogenesis of endometrial cancer

“…In general, it is thought that endometrial cancer develops from atypical endometrial hyperplasia, a precursor lesion of endometrial cancer [32]. Genetic abnormalities or mutations such as p53 mutations, KRAS mutations, phosphatidylinositol 3-kinase (PI3 K) mutations, abnormal PTEN expression, and accumulation of β catenin are known to be involved in malignant transformation of normal endometrium [33,34]. In [ ( F i g .…”

Therapeutic options for management of endometrial hyperplasia

“…The ability of this compound to inhibit uterine growth is attributed to its ability to antagonize estrogen action and apoptosis-inducing activities [ 162 ]. The activity of this compound has also been validated in primary cell culture of human atypical EH cells suggesting its potential use as a new targeted therapy for EH via inhibition of Wnt signaling, as well as inhibition of cell survival pathway [ 163 ].…”