title: 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.
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors.forename: V
authors.initials: V
authors.lastname: Chandra
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors.forename: I
authors.initials: I
authors.lastname: Fatima
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors.forename: M
authors.initials: M
authors.lastname: Manohar
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors.forename: P
authors.initials: P
authors.lastname: Popli
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors.forename: V K
authors.initials: VK
authors.lastname: Sirohi
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors.forename: M K
authors.initials: MK
authors.lastname: Hussain
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors.forename: K
authors.initials: K
authors.lastname: Hajela
authors.affiliation: Department of Obstetrics & Gynecology, King George's Medical University, Lucknow, Uttar Pradesh, India.
authors.forename: P
authors.initials: P
authors.lastname: Sankhwar
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
authors.forename: A
authors.initials: A
authors.lastname: Dwivedi
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000737:chemistry / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004714:Endometrial Hyperplasia / Q000378:metabolism / Q000473:pathology; D004717:Endometrium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000737:chemistry / Q000633:toxicity*; D051157:Frizzled Receptors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010880:Piperidines / Q000737:chemistry / Q000633:toxicity*; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D051153:Wnt Proteins / Q000737:chemistry / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C000600931:2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo(b)pyran; D001578:Benzopyrans; C501126:DKK1 protein, human; C484687:FZD6 protein, human; D005419:Flavonoids; D051157:Frizzled Receptors; D036341:Intercellular Signaling Peptides and Proteins; D010880:Piperidines; D051153:Wnt Proteins; D051176:beta Catenin; D004958:Estradiol; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt