ArticleEndocrinology2013
MK-2206, an AKT inhibitor, promotes caspase-independent cell death and inhibits leiomyoma growth.
Article in Endocrinology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 45 citations in OpenAlex.
- Simvastatin modulates estrogen signaling in uterine leiomyoma via regulating receptor palmitoylation, trafficking and degradation.Pharmacological research · 2021Trial
- UTERINE FIBROIDS.Physiological reviews · 2025Review
- Review
- Review
- New AKT-dependent mechanisms of anti-COVID-19 action of high-CBD Cannabis sativa extracts.Cell death discovery · 2022Article
- Regulation of AKT Signaling in Mouse Uterus.Endocrinology · 2022Article
- Wnt/β-catenin signaling pathway in uterine leiomyoma: role in tumor biology and targeting opportunities.Molecular and cellular biochemistry · 2021Review
- Manganese (II) chloride leads to dopaminergic neurotoxicity by promoting mitophagy through BNIP3-mediated oxidative stress in SH-SY5Y cells.Cellular & molecular biology letters · 2021Article
- Effects of Phthalate Esters on Human Myometrial and Fibroid Cells: Cell Culture and NOD-SCID Mouse Data.Reproductive sciences (Thousand Oaks, Calif.) · 2021Article
- Inhibition of Fibroblast Activation in Uterine Leiomyoma by Components ofFrontiers in public health · 2021Article
- Activation of protein kinase B by WNT4 as a regulator of uterine leiomyoma stem cell function.Fertility and sterility · 2020Article
- SIRT1 promotes pulmonary artery endothelial cell proliferation by targeting the Akt signaling pathway.Experimental and therapeutic medicine · 2020Article
- Ganglioneuromas are driven by activated AKT and can be therapeutically targeted with mTOR inhibitors.The Journal of experimental medicine · 2020Article
- Targeting autophagy-related protein kinases for potential therapeutic purpose.Acta pharmaceutica Sinica. B · 2020Review
- MiR-150-5p May Contribute to Pathogenesis of Human Leiomyoma via Regulation of the Akt/p27International journal of molecular sciences · 2019Article
- Oxidative stress-induced miRNAs modulate AKT signaling and promote cellular senescence in uterine leiomyoma.Journal of molecular medicine (Berlin, Germany) · 2018Article
- Comparative analysis of AKT and the related biomarkers in uterine leiomyomas with MED12, HMGA2, and FH mutations.Genes, chromosomes & cancer · 2018Article
- Concurrent interactome and metabolome analysis reveals role of AKT1 in central carbon metabolism.BMC research notes · 2018Article
- Foxo-dependent Par-4 Upregulation Prevents Long-term Survival of Residual Cells Following PI3K-Akt Inhibition.Molecular cancer research : MCR · 2018Article
- The AKT/BCL-2 Axis Mediates Survival of Uterine Leiomyoma in a Novel 3D Spheroid Model.Endocrinology · 2018Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Uterine leiomyomas (ULs), benign tumors of the myometrium, are the number one indication for hysterectomies in the United States due to a lack of an effective alternative therapy. ULs show activation of the pro-survival AKT pathway compared with normal myometrium; however, substantial data directly linking AKT to UL cell survival are lacking. We hypothesized that AKT promotes UL cell survival and that it is a viable target for inhibiting UL growth. We used the investigational AKT inhibitor MK-2206, currently in phase II trials, on cultured primary human UL and myometrial cells, immortalized leiomyoma cells, and in leiomyoma grafts grown under the kidney capsule in mice. MK-2206 inhibited AKT and PRAS40 phosphorylation but did not regulate serum- and glucocorticoid-induced kinase and ERK1/2, demonstrating its specificity for AKT. MK-2206 reduced UL cell viability and decreased UL tumor volumes. UL cells exhibited disruption of mitochondrial structures and underwent cell death that was independent of caspases. Additionally, mammalian target of rapamycin and p70S6K phosphorylation were reduced, indicating that mammalian target of rapamycin complex 1 signaling was compromised by AKT inhibition in UL cells. MK-2206 also induced autophagy in UL cells. Pretreatment of primary UL cells with 3-methyladenine enhanced MK-2206-mediated UL cell death, whereas knockdown of ATG5 and/or ATG7 did not significantly influence UL cell viability in the presence of MK-2206. Our data provide molecular evidence for the involvement of AKT in UL cell survival and suggest that AKT inhibition by MK-2206 may be a viable option to consider for the treatment of ULs.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.