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


METHODS
Establishment of paired cell cultures of leiomyoma and myometrial specimens.


METHODS
Hadassah gynecology research laboratory.


METHODS
Eleven white premenopausal women, 35 to 50 years of age, undergoing hysterectomy because of symptomatic uterine leiomyomas.


METHODS
None.


METHODS
Immunochemical analysis of expression and phosphorylation of relevant PI3K/Akt and BCL2 proteins.


RESULTS
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 pGSK3alpha 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-pGSK3beta in the leiomyoma compared with the myometrial cells, and [3] there was a significant interaction between pAkt-pGSK3alpha in the paired leiomyoma and myometrial cultures.


CONCLUSIONS
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-pGSK3beta, are involved in the survival and proliferation of leiomyomas.
Karra
Laila
L
Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Ein-Kerem, Jerusalem, Israel.
Shushan
Asher
A
Ben-Meir
Assaf
A
Rojansky
Nathan
N
Klein
Benjamin Y
BY
Shveiky
David
D
Levitzki
Rubina
R
Ben-Bassat
Hanna
H
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000328:Adult; D056742:Cyclin D2 / Q000502:physiology*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D006801:Humans; D007889:Leiomyoma / Q000503:physiopathology*; D008875:Middle Aged; D009215:Myometrium / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D014594:Uterine Neoplasms / Q000503:physiopathology*
D064413:3-Phosphoinositide-Dependent Protein Kinases; D056742:Cyclin D2; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C578562:PDPK1 protein, human; C448021:glycogen synthase kinase 3 alpha; C494929:PTEN protein, human