Inactivation of AKT induces cellular senescence in uterine leiomyoma.
Uterine leiomyomas (fibroids) are a major public health problem. Current medical treatments with GnRH analogs do not provide long-term benefit. Thus, permanent shrinkage or inhibition of fibroid growth via medical means remains a challenge. The AKT pathway is a major growth and survival pathway for fibroids. We propose that AKT inhibition results in a transient regulation of specific mechanisms that ultimately drive cells into cellular senescence or cell death. In this study, we investigated specific mechanisms of AKT inhibition that resulted in senescence. We observed that administration of MK-2206, an allosteric AKT inhibitor, increased levels of reactive oxygen species, up-regulated the microRNA miR-182 and several senescence-associated genes (including p16, p53, p21, and β-galactosidase), and drove leiomyoma cells into stress-induced premature senescence (SIPS). Moreover, induction of SIPS was mediated by HMGA2, which colocalized to senescence-associated heterochromatin foci. This study provides a conceivable molecular mechanism of SIPS by AKT inhibition in fibroids.
Department of Pathology (X.X., J.-J.W.) and Department of Obstetrics and Gynecology (Z.L., W.Q., J.J.K., J.-J.W., V.V.), Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, Illinois; and Department of Obstetrics and Gynecology (X.X., B.K.), Shandong University, Shandong, China.
Xiaofei
X
Xu
Zhenxiao
Z
Lu
Wenan
W
Qiang
Vania
V
Vidimar
Beihua
B
Kong
J Julie
JJ
Kim
Jian-Jun
JJ
Wei
D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D025743:HMGA2 Protein / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry; D006801:Humans; D007889:Leiomyoma / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism; D009215:Myometrium / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000502:physiology; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D015854:Up-Regulation; D014594:Uterine Neoplasms / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism
D025743:HMGA2 Protein; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D035683:MicroRNAs; C538984:Mirn182 microRNA, human; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D001616:beta-Galactosidase