Progestins Activate the AKT Pathway in Leiomyoma Cells and Promote Survival

Hoekstra, Anna V.; Sefton, Elizabeth C.; Berry, Emily; Lu, Zhenxiao; Hardt, Jennifer; Marsh, Erica E.; Yin, Ping; Clardy, Jon; Chakravarti, Debabrata; Bulun, Serdar E.; Kim, Julie

doi:10.1210/jc.2008-2093

Cited by 79 publications

(51 citation statements)

References 34 publications

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“…They also demonstrated that progesterone upregulates expression of proliferating cell nuclear antigen (PCNA) and epidermal growth factor (EGF), both are known regulators of leiomyoma cellular proliferation (58,59). Furthermore, Hoekstra and colleagues (60) demonstrated that R5020 (a synthetic progestin that acts as an agonist of progesterone receptors) induces proliferation of leiomyoma cells in vitro. In addition, they found that R5020 activates (through phosphorylation) AKT and glycogen synthase kinase-3B (GSK3B).…”

Section: Progesteronementioning

confidence: 99%

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Borahay

Al-Hendy

Kılıç

et al. 2015

Mol Med

128

147

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Uterine leiomyomas are the most common tumors of the female genital tract, affecting 50% to 70% of females by the age of 50. Despite their prevalence and enormous medical and economic impact, no effective medical treatment is currently available. This is, in part, due to the poor understanding of their underlying pathobiology. Although they are thought to start as a clonal proliferation of a single myometrial smooth muscle cell, these early cytogenetic alterations are considered insufficient for tumor development and additional complex signaling pathway alterations are crucial. These include steroids, growth factors, transforming growth factor-beta (TGF-β)/Smad; wingless-type (Wnt)/β-catenin, retinoic acid, vitamin D, and peroxisome proliferator-activated receptor γ (PPARγ). An important finding is that several of these pathways converge in a summative way. For example, mitogen-activated protein kinase (MAPK) and Akt pathways seem to act as signal integrators, incorporating input from several signaling pathways, including growth factors, estrogen and vitamin D. This underlines the multifactorial origin and complex nature of these tumors. In this review, we aim to dissect these pathways and discuss their interconnections, aberrations and role in leiomyoma pathobiology. We also aim to identify potential targets for development of novel therapeutics.

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Section: Progesteronementioning

confidence: 99%

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Borahay

Al-Hendy

Kılıç

et al. 2015

Mol Med

128

147

View full text Add to dashboard Cite

show abstract

“…Progesterone-bound PR dimers are translocated to the nucleus, bind to DNA, recruit cofactors, and induce B-cell lymphoma 2 (Bcl-2) gene expression [12] in a so-called genomic signaling pathway. Discovered some time later, non-genomic (purely cytoplasmic) signaling of PR regulates Akt pathway activation [13]. …”

Section: Introductionmentioning

confidence: 99%

Progesterone Receptor Isoforms, Nuclear Corepressor-1 and Steroid Receptor Coactivator-1 and B-Cell Lymphoma 2 and Akt and Akt Phosphorylation Status in Uterine Myomas after Ulipristal Acetate Treatment: A Systematic Immunohistochemical Evaluation

Courtoy

Donnez

Marbaix

et al. 2017

Gynecol Obstet Invest

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Objective: To investigate whether ulipristal acetate (UPA) treatment modifies the expression of progesterone receptor (PR), its nuclear cofactors steroid receptor coactivator-1 (SRC1) and nuclear corepressor-1 (NCoR1), prosurvival factor B-cell lymphoma 2 (Bcl-2), and Akt in uterine myomas. Patients: Prospective study of 59 women with symptomatic myomas undergoing myomectomy. Forty-two patients were treated preoperatively with UPA; the remaining 17 were not and they served as controls. Method: Tissue microarrays were obtained from surgical specimens and immunohistochemistry was performed. Blinded quantification of expression of PR (PR-A vs. PR-B), coactivator SRC1 and corepressor NCoR1, and prosurvival factor Bcl-2, and Akt and evaluation of Akt phosphorylation levels. Results: Compared with the control group, UPA does not alter PR protein levels or expression patterns in myomas, and the PR-A/PR-B ratio was similar, as well as cytoplasmic or nuclear expression of cofactors SRC1 and NCoR1. Bcl-2 was heterogeneously expressed throughout the samples and no significant modification in expression was evidenced. No significant difference was found in Akt expression and phosphorylation between treated and untreated myomas. Conclusion: This study did not find any significant change in the expression of the studied factors in myomas after UPA exposure. In conclusion, various theories on myomas cells proposed on the basis of in vitro studies are not supported in vivo.

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“…PI3K generates phosphatidylinositol-(3,4,5)-triphosphate (PIP3), which in turn activates 3-phosphoinositide-dependent protein kinase 1 (PDK1). PDK1 then activates protein kinase B (PKB/Akt) [16,17]. Apoptosis signaling involves cysteine aspartate-specific protease (caspase)-dependent and -independent apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of the Integrin α<sub><i>v</i></sub> Signaling Pathway in Uterine Leiomyomas

Tsai

Liu

Pai³

et al. 2010

Gynecol Obstet Invest

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Objective: To investigate alterations of integrin α_v, survival and apoptosis signaling pathways in uterine leiomyomas. Materials and Methods: In a prospective study of 50 women with uterine leiomyomas that had been pathologically confirmed, specimens were obtained laparoscopically from 2007 to 2009. The expressions of integrin α_v signaling pathways (Ras/Raf/ERK1/2, Akt and cleaved caspase-3), surface microstructures by surface electron microscopy and immunohistochemical findings were assessed. Results: The study yielded novel results: (1) the integrin α_v expression approached a low level (mRNA 0.39 ± 0.06, protein 0.47 ± 0.08) with coherent alterations of its downstream signaling molecules (Ras, p-c-Raf, p-ERK1/2) (p < 0.001); (2) smoother surface microstructures of uterine leiomyomas were correlated with low integrin α_v expressions, and (3) survival signaling and apoptosis signaling were significantly down- and upregulated respectively (p < 0.001). Conclusion: Integrin α_v and related survival signaling pathways were downregulated, but the apoptosis was upregulated in uterine leiomyomas. Benign smooth-contoured tumors may have low integrin expressions and cancer invasion potentials.

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Progestins Activate the AKT Pathway in Leiomyoma Cells and Promote Survival

Abstract: The progestin, R5020, can rapidly activate the AKT pathway. Inhibition of the AKT pathway inhibits cell proliferation and promotes apoptosis of leiomyoma cells.

Cited by 79 publications

References 34 publications

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Signaling Pathways in Leiomyoma: Understanding Pathobiology and Implications for Therapy

Progesterone Receptor Isoforms, Nuclear Corepressor-1 and Steroid Receptor Coactivator-1 and B-Cell Lymphoma 2 and Akt and Akt Phosphorylation Status in Uterine Myomas after Ulipristal Acetate Treatment: A Systematic Immunohistochemical Evaluation

Downregulation of the Integrin α<sub><i>v</i></sub> Signaling Pathway in Uterine Leiomyomas

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