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Targeting leiomyomas with all‐trans‐retinoic acid at phosphoinositide 3‐kinase pathway suppression: Effective roles of β‐catenin and of signaling interactions
Author(s) -
Friedman Noa,
Shushan Asher,
Rojansky Nathan,
Shveiky David,
Levitzki Rubina,
Chaouat Malka,
BenBassat Hannah
Publication year - 2016
Publication title -
journal of obstetrics and gynaecology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.597
H-Index - 50
eISSN - 1447-0756
pISSN - 1341-8076
DOI - 10.1111/jog.13068
Subject(s) - pi3k/akt/mtor pathway , uterine leiomyoma , signal transduction , retinoic acid , leiomyoma , phosphoinositide 3 kinase , medicine , cancer research , cell growth , microbiology and biotechnology , endocrinology , biology , pathology , cell culture , biochemistry , genetics
Abstract Aim Leiomyomas, monoclonal tumors developed by the transformation of myometrium somatic stem cells, are a major health concern that can severely impair quality of life. Pathological alterations of signaling pathways have been recognized as a key feature in a variety of human diseases. Our objective was to analyze treatment with all‐trans‐retinoic acid (ATRA) by suppression of the phosphoinositide 3‐kinase (PI3K) pathway on growth, signaling pattern and interactions among PI3K/B‐cell lymphoma 2 (Bcl2)/retinol leiomyoma proteins. Methods Cultures of paired myometrium and leiomyoma cells from premenopausal women undergoing hysterectomy were collected. Western blot and analysis of variance were used for analysis. Results Significant differences were detected between treatment with ATRA alone or with LY294002 (a PI3K growth suppressor) in response to treatment and among cell samples and cell numbers. Leiomyoma cells were less affected. Immunochemical analysis of signaling patterns demonstrated that treatments affected most of the examined protein levels differently. Significant differences between the cell type responses to treatment in pyruvate phosphate dikinase 1 (pPDK1), Bad and pβ‐catenin levels were identified. The pβ‐catenin level showed highly significant interaction between response to treatment and cell type. Conclusions ATRA treatment on PI3K pathway suppression significantly affected growth, signaling pattern and interactions among PI3K/Bcl2/retinol proteins involved in the growth, survival and apoptosis of leiomyomas. Interpretation of our results suggests that increasing knowledge of the role of signaling interplay in the pathogenesis of leiomyomas may present an opportunity to use specific signal transduction inhibitors for treating and preventing this disorder.