Changes related to phosphatidylinositol 3-kinase/Akt signaling in leiomyomas: possible involvement of glycogen synthase kinase 3α and cyclin D2 in the pathophysiology

ObjectiveTo identify changes in the expression and phosphorylation of phosphatidylinositol 3-kinase (PI3K)/Akt protein kinases controlling survival and/or apoptosis of in vitro cell cultures of uterine leiomyomas.DesignEstablishment of paired cell cultures of leiomyoma and myometrial specimens.SettingHadassah gynecology research laboratory.Patient(s)Eleven white premenopausal women, 35 to 50 years of age, undergoing hysterectomy because of symptomatic uterine leiomyomas.Intervention(s)None.Main Outcome Measure(s)Immunochemical analysis of expression and phosphorylation of relevant PI3K/Akt and BCL2 proteins.Result(s)Analysis of total phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and of nonphosphorylated and phosphorylated (p) PDK1, Akt, glycogen synthase kinase 3 (GSK3), FKHR, tuberin (TSC2) and hamartin (TSC1) complex, and cyclin D2 proteins indicated that [1] the level of pGSK3α and cyclin D2 proteins was elevated significantly in the leiomyoma compared with the normal myometrium, [2] there was a significant interaction between PTEN- PDK1 and between pAkt-pGSK3β in the leiomyoma compared with the myometrial cells, and [3] there was a significant interaction between pAkt-pGSK3α in the paired leiomyoma and myometrial cultures.Conclusion(s)Our study suggests that the downstream signaling components of the PI3K/Akt pathway, GSK3 (a regulator of apoptosis), and cyclin D2 (a promoter of G1/S progression), as well as the significant interaction between PTEN-PDK and between pAkt-pGSK3β, are involved in the survival and proliferation of leiomyomas.