Estrogen receptor β agonist enhances temozolomide sensitivity of glioma cells by inhibiting PI3K/AKT/mTOR pathway

Liu, Xiaoyang; Wang, Libo; Chen, Jiajun; Ling, Qi; Wang, Hongfei; Li, Shilin; Li, Liming; Yang, Shuping; Xia, Mingxu; Jing, Ling

doi:10.3892/mmr.2014.2811

Cited by 31 publications

(35 citation statements)

References 38 publications

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“…On the other hand, in melanoma cells harboring BRAF mutations, only the MEK/ERK signaling cascade was shown to be overactivated. In agreement with our data, ERβ ligands have been previously shown to exert their antitumor effects through inactivation of RAS as well as of the PI3K/Akt pathway in some cancer cells (94, 141, 142). Moreover, Wang and coworkers (143) have recently reported an inverse correlation between the expression of ERβ and the activity of the PI3K/Akt pathway in aggressive, triple-negative, breast cancer.…”

Section: Antitumor Activity Of Erβ In Melanomasupporting

confidence: 92%

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Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

et al. 2016

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Cutaneous melanoma is an aggressive tumor; its incidence has been reported to increase fast in the past decades. Melanoma is a heterogeneous tumor, with most patients harboring mutations in the BRAF or NRAS oncogenes, leading to the overactivation of the MAPK/ERK and PI3K/Akt pathways. The current therapeutic approaches are based on therapies targeting mutated BRAF and the downstream pathway, and on monoclonal antibodies against the immune checkpoint blockade. However, treatment resistance and side effects are common events of these therapeutic strategies. Increasing evidence supports that melanoma is a hormone-related cancer. Melanoma incidence is higher in males than in females, and females have a significant survival advantage over men. Estrogens exert their effects through estrogen receptors (ERα and ERβ) that affect cancer growth in an opposite way: ERα is associated with a proliferative action and ERβ with an anticancer effect. ERβ is the predominant ER in melanoma, and its expression decreases in melanoma progression, supporting its role as a tumor suppressor. Thus, ERβ is now considered as an effective molecular target for melanoma treatment. 17β-estradiol was reported to inhibit melanoma cells proliferation; however, clinical trials did not provide the expected survival benefits. In vitro studies demonstrate that ERβ ligands inhibit the proliferation of melanoma cells harboring the NRAS (but not the BRAF) mutation, suggesting that ERβ activation might impair melanoma development through the inhibition of the PI3K/Akt pathway. These data suggest that ERβ agonists might be considered as an effective treatment strategy, in combination with MAPK inhibitors, for NRAS mutant melanomas. In an era of personalized medicine, pretreatment evaluation of the expression of ER isoforms together with the concurrent oncogenic mutations should be considered before selecting the most appropriate therapeutic intervention. Natural compounds that specifically bind to ERβ have been identified. These phytoestrogens decrease the proliferation of melanoma cells. Importantly, these effects are unrelated to the oncogenic mutations of melanomas, suggesting that, in addition to their ERβ activating function, these compounds might impair melanoma development through additional mechanisms. A better identification of the role of ERβ in melanoma development will help increase the therapeutic options for this aggressive pathology.

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Section: Antitumor Activity Of Erβ In Melanomasupporting

confidence: 92%

“…Moreover, LQ treatment significantly inhibits the activity of the PI3K/Akt pathway, and this effect is completely reversed by ERβ knockdown (142). …”

Section: Natural Erβ Ligands and Melanomamentioning

confidence: 99%

Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

et al. 2016

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“…We also demonstrated that siRNA-mediated silencing of ERβ abrogated its cytotoxicity. These data are consistent with the general notion that ERβ is a tumor suppressor and that selective ERβ agonists are candidates for anti-cancer drugs [32,33]. According to our study, TSN seems to have no desirable effect on ERα even though ERα and ERβ are structurally similar.…”

Section: Discussionsupporting

confidence: 92%

Toosendanin Exerts an Anti-Cancer Effect in Glioblastoma by Inducing Estrogen Receptor β- and p53-Mediated Apoptosis

Cao

Wang

et al. 2016

IJMS

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Glioblastoma (GBM) is the most common primary brain tumor with median survival of approximately one year. This dismal poor prognosis is due to resistance to currently available chemotherapeutics; therefore, new cytotoxic agents are urgently needed. In the present study, we reported the cytotoxicity of toosendanin (TSN) in the GBM U87 and C6 cell lines in vitro and in vivo. By using the MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay, flow cytometry analysis, and Western blot, we found that TSN inhibited U87 and C6 cell proliferation and induced apoptosis at a concentration as low as 10 nM. Administration of TSN also reduced tumor burden in a xenograft model of athymic nude mice. Pharmacological and molecular studies suggested that estrogen receptor β (ERβ) and p53 were prominent targets for TSN. GBM cell apoptosis induced by TSN was a stepwise biological event involving the upregulation of ERβ and contextual activation of functional p53. Collectively, our study indicates, for the first time, that TSN is a candidate of novel anti-cancer drugs for GBM. Furthermore, ERβ and p53 could act as predictive biomarkers for the sensitivity of cancer to TSN.

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“…Upon activation, mTOR can phosphorylate its two downstream molecules, namely translation-inhibition molecule EIF-4E binding protein 1 (4E-BP1) and ribosomal protein p70S6K. As 4E-BP1 is inactivated through phosphorylation, its ability to bind to EIF-4E is lost and results in the dissociation of the complex and the combination of EIF-4E with other translation initiation factors to induce protein translation (24). Following phosphorylative activation of p70S6K, protein synthesis is enhanced.…”

Section: Discussionmentioning

confidence: 99%

Silybin suppresses cell proliferation and induces apoptosis of multiple myeloma cells via the PI3K/Akt/mTOR signaling pathway

Feng

Luo

Guo

2016

Molecular Medicine Reports

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Abstract. Silybin is a biologically active component extracted from the seeds of Silybum marianum, which has been shown to have inhibitory effects on prostate, skin, bladder, lung and colon cancer cells, in addition to its efficacy in the treatment of liver diseases, including hepatitis and cirrhosis. The aim of the present study was to investigate whether silybin suppresses the proliferation and induces apoptosis of multiple myeloma (MM) cells and to elucidate its molecular targets. The proliferative and apoptotic rates of the U266 MM cell line were assessed using MTT and flow-cytometric assays, respectively. Western blot analysis was used to assess the protein levels of phosphoinositide-3 kinase (PI3K), phosphorylated (p)-Akt and p-mammalian target of rapamycin (mTOR) in U266 cells. In addition, PI3K inhibitor LY294002 or activator insulin-like growth factor 1 were used to investigate the involvement of the PI3K/Akt-mTOR signaling pathway in the effect of silybin on U266 cells. The results revealed that silybin restrained the proliferation and enhanced the apoptosis of U266 cells. Furthermore, silybin inhibited the protein expression of PI3K, p-Akt and p-mTOR in U266 cells. Of note, inhibition of PI3K facilitated silybin-mediated reduction of mTOR activation, cell proliferation and induction of apoptosis in U266 cells, while activation of PI3K attenuated the effects of silybin. In conclusion, silybin suppressed cell proliferation and promoted apoptosis of U266 cells via PI3K/Akt-mTOR signaling pathways.

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Estrogen receptor β agonist enhances temozolomide sensitivity of glioma cells by inhibiting PI3K/AKT/mTOR pathway

Cited by 31 publications

References 38 publications

Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

Toosendanin Exerts an Anti-Cancer Effect in Glioblastoma by Inducing Estrogen Receptor β- and p53-Mediated Apoptosis

Silybin suppresses cell proliferation and induces apoptosis of multiple myeloma cells via the PI3K/Akt/mTOR signaling pathway

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