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Oxidative stress-induced miRNAs modulate AKT signaling and promote cellular senescence in uterine leiomyoma.

ABSTRACT: Uterine leiomyomas (ULM) grow under high oxidative stress due to a hypoxic microenvironment and defects in redox metabolism. AKT is one major pathway activated by reactive oxygen species (ROS) that maintains ULM growth and survival. We previously reported that AKT inactivated by AKT inhibitors can significantly induce cellular senescence in ULM cells. Since some miRNAs are induced by AKT inhibitors in an ROS-dependent manner, we proposed that these miRNAs may modulate AKT function and cellular senescence in ULM. We therefore established ex vivo models of a three-dimensional ULM spheroid culture system to study the role of miRNAs in cellular senescence. Four miRNAs, miR-29b, miR-181a, miR-182, and miR-200c, were found to induce cellular senescence in primary ULM and myometrium spheroid cultures when stably overexpressed. miR-181a and miR-182 were found to repress AKT3 and CCND2, respectively. Correspondingly, RNAi of AKT3 or CCND2 also induced cellular senescence and G0/G1 arrest. Thus, miR-181a and miR-182 may drive cellular senescence in ULM by repressing AKT3 and CCND2 activity, respectively. We further demonstrated that senescent ULM cells can be effectively removed by BH3 mimetic ABT263, which provides a new therapeutic venue for the treatment of ULM. Our findings suggest that miRNAs are potent modulators in regulating the ROS-AKT-cell cycle axis in uterine leiomyoma. KEY MESSAGES:A subset of oxidative stress-induced miRNAs is involved in AKT signaling in uterine leiomyoma. Overexpression of miR-181a and miR-182 resulted in cellular senescence in leiomyoma through repression of AKT3 and CCND2, respectively. Silencing of AKT3 and CCND2 drives leiomyoma cell into senescence and cycle arrest. Application of our newly developed 3D leiomyoma spheroids can provide a quick and reliable ex vivo model for cytopathologic and functional analysis. BH3 mimetics can effectively reduce the viability of miRNA-mediated senescent cells in leiomyoma.

SUBMITTER: Xu X

PROVIDER: S-EPMC6135677 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Oxidative stress-induced miRNAs modulate AKT signaling and promote cellular senescence in uterine leiomyoma.

Xu Xiuhua X Kim J Julie JJ Li Yinuo Y Xie Jia J Shao Changshun C Wei Jian-Jun JJ

Journal of molecular medicine (Berlin, Germany) 20180810 10

Uterine leiomyomas (ULM) grow under high oxidative stress due to a hypoxic microenvironment and defects in redox metabolism. AKT is one major pathway activated by reactive oxygen species (ROS) that maintains ULM growth and survival. We previously reported that AKT inactivated by AKT inhibitors can significantly induce cellular senescence in ULM cells. Since some miRNAs are induced by AKT inhibitors in an ROS-dependent manner, we proposed that these miRNAs may modulate AKT function and cellular s ...[more]

PMID: 30097674

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Project description:Both environmental exposure to vanadium pentoxide (V2O5, V+5 for its ionic counterparts) and fibroblast senescence are associated with pulmonary fibrosis, but whether V+5 causes fibroblast senescence remains unknown. We found in a dose-response study that 2-40 μM V+5 caused human lung fibroblasts (HLF) senescence with increased senescence-associated β-galactosidase activity and p16 expression, while cell death occurred at higher concentration (LC50, 82 μM V+5). Notably, measures of reactive oxygen species (ROS) production with fluorescence probes showed no association of ROS with V+5-dependent senescence. Preloading catalase (polyethylene-conjugated), a H2O2 scavenger, did not alleviate the cellular senescence induced by V+5. Analyses of the cellular glutathione (GSH) system showed that V+5 oxidized GSH, increased GSH biosynthesis, stimulated cellular GSH efflux and increased protein S-glutathionylation, and addition of N-acetyl cysteine inhibited V+5-elevated p16 expression, suggesting that thiol oxidation mediates V+5-caused senescence. Moreover, strong correlations between GSSG/GSH redox potential (Eh), protein S-glutathionylation, and cellular senescence (R2 > 0.99, p < 0.05) were present in V+5-treated cells. Studies with cell-free and enzyme-free solutions showed that V+5 directly oxidized GSH with formation of V+4 and GSSG in the absence of O2. Analyses of V+5 and V+4 in HLF and culture media showed that V+5 was reduced to V+4 in cells and that a stable V+4/V+5 ratio was rapidly achieved in extracellular media, indicating ongoing release of V+4 and reoxidation to V+5. Together, the results show that V+5-dependent fibroblast senescence is associated with a cellular/extracellular redox cycling mechanism involving the GSH system and occurring under conditions that do not cause cell death. These results establish a mechanism by which environmental vanadium from food, dietary supplements or drinking water, can cause or contribute to lung fibrosis in the absence of high-level occupational exposures and cytotoxic cell death.

Dataset Information

Oxidative stress-induced miRNAs modulate AKT signaling and promote cellular senescence in uterine leiomyoma.

Publications

Oxidative stress-induced miRNAs modulate AKT signaling and promote cellular senescence in uterine leiomyoma.

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