The anti-proliferative effect of 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b) pyran is potentiated via induction of estrogen receptor beta and p21 in human endometrial adenocarcinoma cells

Fatima, Iram; Saxena, Ruchi; Kharkwal, Geetika; Hussain, Mohammad Kamil; Yadav, Nisha; Sankhwar, Pushp Lata; Dwivedi, Anila

doi:10.1016/j.jsbmb.2013.04.005

Cited by 15 publications

(12 citation statements)

References 32 publications

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“…This appears to be the case in our study. In contrast to previous studies (25,29), we also reported an enhancement of cell migration and proliferation exerted by ERβ. Although this information did not allow for a complete discussion of the role of ERβ in endometrial carcinoma, these data strongly indicate that ERβ could be associated with an aggressive phenotype.…”

Section: Discussioncontrasting

confidence: 99%

“…6, upregulation of ERα resulted in an observable increase of cell proliferative activity compared with the control group. Contrary to some previous studies (24,25), we also found the promoted proliferation effect exerted by ERβ. Moreover, enhanced effect of cell growth was more significant after ERα transfection, as compared with cells transfected with ERβ expression vector.…”

Section: Effects Of Overexpression Of Erα and Erβ On Cell Proliferationcontrasting

confidence: 99%

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Upregulation of estrogen receptor mediates migration, invasion and proliferation of endometrial carcinoma cells by regulating the PI3K/AKT/mTOR pathway

et al. 2013

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The precise mechanism through which the two estrogen receptor subtypes, ERα and ERβ, are linked to endometrial malignant progression is not fully understood. The aim of the present study was to examine their role in endometrial carcinoma cell migration, invasion and proliferation. We also explored the correlation between the ERs and phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathways in endometrial carcinoma cells. Using Ishikawa and KLE cells as model systems, we performed transient transfection to upregulate ERα and ERβ expression; fluorescence microscopy analysis was then employed to evaluate transfection efficiencies, RT-PCR and western blot assays were used to evaluate the mRNA and protein levels. We further examined the effects on cell migration, invasion and proliferation. We showed that ERα raised the phosphorylation levels of PI3K p85α, activated the phosphorylation of AKT and mTOR in Ishikawa and KLE cells, but ERβ had no effect on PI3K p85α phosphorylation. Moreover, the overexpression of ERs enhanced cell migration, invasion and proliferation. The effect on the activation of the PI3K/AKT/mTOR transduction cascade by ERα explains, at least in part, the enhancement on cell invasion and proliferation exerted by overexpression of ERα. This crosstalk could be taken into account in developing novel therapeutic methods by targeting the ERα and PI3K/AKT/mTOR pathways in endometrial carcinoma.

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Section: Discussioncontrasting

confidence: 99%

Section: Effects Of Overexpression Of Erα and Erβ On Cell Proliferationcontrasting

confidence: 99%

Upregulation of estrogen receptor mediates migration, invasion and proliferation of endometrial carcinoma cells by regulating the PI3K/AKT/mTOR pathway

et al. 2013

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“…It competes with estradiol for binding to both hER α and hER β indicating its interaction with both ER subtypes. 17 We have earlier shown that K-1 inhibits classical and non-classical estrogen signaling in uterus. 15 , 16 Because Wnt signaling pathway is known to be regulated via estrogen, we explored further whether K-1 is able to suppress the estrogen-induced Wnt signaling in human endometrial cells.…”

Section: Discussionmentioning

confidence: 96%

“…Besides, in hyperplasial cells, the aberrant endogenously synthesized E may be responsible for higher ER expression. Because K-1 is already known to interact with ERs, and antagonize the action of E, 14 , 17 it might cause the inhibition of estrogen-induced signaling mechanism in normal endometrial cells when exogenous E was given.…”

Section: Discussionmentioning

confidence: 99%

“…In our prior studies, it has been demonstrated that benzopyrans are the class of potent antiestrogenic compounds 13 , 14 that showed antiproliferative and apoptotic activity in rat endometrial hyperplasia 15 and in human endometrial cancer cells. 16 , 17 However, the complete mechanism of action of 2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo(b)pyran (K-1), responsible for inhibition of endometrial hyperplasia, remains to be explored in human endometrial hyperplasial cells. Because estrogen is one of the factor responsible for inducing Wnt/ β -catenin signaling that may be responsible for inducing proliferation and hyperplasia formation in endometrium, 4 , 5 we further analyzed whether the benzopyran compound (K-1) modulates Wnt/ β -catenin signaling in human endometrial hyperplasial cells from proliferation (Wnt-On) to differentiation (Wnt-Off).…”

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Inhibitory effect of 2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo(b)pyran (K-1) on human primary endometrial hyperplasial cells mediated via combined suppression of Wnt/β-catenin signaling and PI3K/Akt survival pathway

et al. 2014

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Endometrial hyperplasia is a precursor to the most common gynecologic cancer diagnosed in women. Apart from estrogenic induction, aberrant activation of the Wnt/β-catenin signal is well known to correlate with endometrial hyperplasia and its carcinoma. The benzopyran compound 2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo (b) pyran(K-1), a potent antiestrogenic agent, has been shown to have apoptosis-inducing activity in rat uterine hyperplasia. The current study was undertaken to explore the effect of the benzopyran compound K-1 on growth and Wnt signaling in human endometrial hyperplasial cells. Primary culture of atypical endometrial hyperplasial cells was characterized by the epithelial cell marker cytokeratin-7. Results revealed that compound K-1 reduced the viability of primary endometrial hyperplasial cells and expression of ERα, PR, PCNA, Wnt7a, FZD6, pGsk3β and β-catenin without affecting the growth of the primary culture of normal endometrial cells. The β-catenin target genes CyclinD1 and c-myc were also found to be reduced, whereas the expression of axin2 and Wnt/β-catenin signaling inhibitor Dkk-1 was found to be upregulated, which caused the reduced interaction of Wnt7a and FZD6. Nuclear accumulation of β-catenin was found to be decreased by compound K-1. K-1 also suppressed the pPI3K/pAkt survival pathway and induced the cleavage of caspases and PARP, thus subsequently causing the apoptosis of endometrial hyperplasial cells. In conclusion, compound K-1 suppressed the growth of human primary endometrial hyperplasial cells through discontinued Wnt/β-catenin signaling and induced apoptosis via inhibiting the PI3K/Akt survival pathway.

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Effect of 2‐methoxyestradiol on mammary tumor initiation and progression

Peta,

Durandt,

van Heerden

et al. 2024

Cancer Reports

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BackgroundThe anti‐cancer agent 2‐methoxyestradiol (2‐ME) has been shown to have anti‐proliferative and anti‐angiogenic properties. Previously, the effect of 2‐ME on early‐ and late‐stage breast cancer (BC) was investigated in vivo using a transgenic mouse model (FVB/N‐Tg(MMTV‐PyVT)) of spontaneous mammary carcinoma. Anti‐tumor effects were observed in late‐stage BC with no effect on early‐stage BC. Given the contrasting results obtained from the different BC stages, we have now investigated the effect of 2‐ME when administered before the appearance of palpable tumors.MethodsEach mouse received 100 mg/kg 2‐ME on day 30 after birth, twice per week for 28 days, while control mice received vehicle only. Animals were terminated on day 59. Lung and mammary tissue were obtained for immunohistochemical analysis of CD163 and CD3 expression, and histological examination was performed to analyze tumor necrosis. Additionally, blood samples were collected to measure plasma cytokine levels.Results2‐ME increased tumor mass when compared to the untreated animals (p = .0139). The pro‐tumorigenic activity of 2‐ME was accompanied by lower CD3+ T‐cell numbers in the tumor microenvironment (TME) and high levels of the pro‐inflammatory cytokine interleukin (IL)‐1β. Conversely, 2‐ME‐treatment resulted in fewer CD163+ cells detectable in the TME, increased levels of tumor necrosis, increased IL‐10 plasma levels, and low IL‐6 and IL‐27 plasma levels.ConclusionTaken together, these findings suggest that 2‐ME promotes early‐stage BC development.

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The anti-proliferative effect of 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b) pyran is potentiated via induction of estrogen receptor beta and p21 in human endometrial adenocarcinoma cells

Cited by 15 publications

References 32 publications

Upregulation of estrogen receptor mediates migration, invasion and proliferation of endometrial carcinoma cells by regulating the PI3K/AKT/mTOR pathway

Upregulation of estrogen receptor mediates migration, invasion and proliferation of endometrial carcinoma cells by regulating the PI3K/AKT/mTOR pathway

Inhibitory effect of 2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo(b)pyran (K-1) on human primary endometrial hyperplasial cells mediated via combined suppression of Wnt/β-catenin signaling and PI3K/Akt survival pathway

Effect of 2‐methoxyestradiol on mammary tumor initiation and progression

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