All-trans-retinoic acid mediates changes in PI3K and retinoic acid signaling proteins of leiomyomas

Objective: To detect changes induced by all-trans-retinoic acid (ATRA) on the expression and activation of target proteins of the retinoic acid (RA) and PI3K/Akt pathways involved in leiomyoma growth. Design: A study on human tissue cultures. Setting: Hadassah University Hospital. Patient(s): Premenopausal women with uterine leiomyomas. Intervention(s): Paired cultures of normal myometrium and leiomyomas, from women undergoing hysterectomy, were obtained. Main Outcome Measure(s): The effect of ATRA was examined on the expression and phosphorylation of relevant RA, PI3K/Akt, and Bcl2 proteins (immunochemical analysis), cell proliferation, cell cycle distribution, and apoptosis. Result(s): Applying our cell culture model, we demonstrated that ATRA induced changes in the expression and activation of the RA and PI3K/Akt pathway proteins in leiomyoma cells, with significant increases of alcohol dehydrogenase 1 and cyclin D2 protein levels. In part of the leiomyoma cells, ATRA induced a relative increase of Bax (proapoptotic) as well as a relative decrease of phosphorylated glycogen synthase kinase 3b (proapoptotic). Conclusion(s): Our results highlight the involvement of ATRA in the RA and PI3K/Akt pathways, whose specific signaling products may influence the outcome of leiomyoma growth by regulating cell proliferation, apoptosis, and survival. These results might be useful for the on-going research into alternative methods for treating and preventing this disorder. (Fertil Steril (R) 2011; 95:2080-6. (C) 2011 by American Society for Reproductive Medicine.)