title: Dysfunctional MnSOD leads to redox dysregulation and activation of prosurvival AKT signaling in uterine leiomyomas.
abstract: AKT signaling promotes cell growth and survival and is often dysregulated via multiple mechanisms in different types of cancer, including uterine leiomyomas (ULMs). ULMs are highly prevalent fibrotic tumors that arise from the smooth muscular layer of the uterus, the myometrium (MM). ULMs pose a major public health issue because they can cause severe morbidity and poor pregnancy outcomes. ‬We investigate the mechanisms driving ULM growth and survival via aberrant activation of AKT. We demonstrate that an acetylation-mediated impairment of the manganese superoxide dismutase (MnSOD) activity is prevalent in ULM cells compared to the normal-matched MM from the same patients. This impairment increases the levels of superoxide and oxidative stress, which activate AKT via oxidative inactivation of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Redox activation of AKT promotes ULM cell survival under conditions of moderate but persistent oxidative stress that are compatible with ULM's prooxidative microenvironment. Moreover, because of impaired MnSOD activity, ULM cells are sensitive to high levels of reactive oxygen species (ROS) and superoxide-generating compounds, resulting in decreased ULM cell viability. On the contrary, MM cells with functional MnSOD are more resistant to high levels of oxidants. This study demonstrates a causative role of acetylation-mediated MnSOD dysfunction in activating prosurvival AKT signaling in ULMs. The specific AKT and redox states of ULM cells provide a potential novel therapeutic rationale to selectively target ULM cells because of their defective ROS-scavenging system.‬‬‬‬‬‬‬‬.
authors.affiliation: Division of Reproductive Science and Medicine, Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60610, USA.
authors.forename: Vania
authors.initials: V
authors.lastname: Vidimar
authors.affiliation: Department of Radiation Oncology, Northwestern University, Chicago, IL 60610, USA.
authors.forename: David
authors.initials: D
authors.lastname: Gius
authors.affiliation: Division of Reproductive Science and Medicine, Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60610, USA.
authors.forename: Debabrata
authors.identifier: 0000-0001-8446-8599
authors.initials: D
authors.lastname: Chakravarti
authors.affiliation: Division of Reproductive Science and Medicine, Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60610, USA.
authors.forename: Serdar E
authors.initials: SE
authors.lastname: Bulun
authors.affiliation: Division of Reproductive Science and Medicine, Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60610, USA.; Department of Pathology, Northwestern University, Chicago, IL 60610, USA.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Wei
authors.affiliation: Division of Reproductive Science and Medicine, Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL 60610, USA.
authors.forename: J Julie
authors.initials: JJ
authors.lastname: Kim
mesh_terms: D000328:Adult; D002470:Cell Survival; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007889:Leiomyoma / Q000201:enzymology* / Q000473:pathology; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D013482:Superoxide Dismutase; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: AKT; MnSOD; ROS; fibroids; leiomyoma