Interplay between steroid hormone activation of the unfolded protein response and nuclear receptor action

Zheng, Xiaobin; Andruska, Neal; Yu, Liqun; Mao, Chengjian; Kim, Ji Eun; Livezey, Mara R.; Helferich, William G.; Shapiro, David J.

doi:10.1016/j.steroids.2016.03.014

Cited by 16 publications

(12 citation statements)

References 49 publications

(63 reference statements)

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“…E 2 elicits a weak anticipatory activation of the UPR that is a strong prognostic marker correlated with tamoxifen resistance 20 24 29 . The effect of P 4 on the UPR had not been explored.…”

Section: Resultsmentioning

confidence: 99%

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Antiestrogen Resistant Cell Lines Expressing Estrogen Receptor α Mutations Upregulate the Unfolded Protein Response and are Killed by BHPI

Mao

Livezey

Kim

et al. 2016

Sci Rep

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Outgrowth of metastases expressing ERα mutations Y537S and D538G is common after endocrine therapy for estrogen receptor α (ERα) positive breast cancer. The effect of replacing wild type ERα in breast cancer cells with these mutations was unclear. We used the CRISPR-Cas9 genome editing system and homology directed repair to isolate and characterize 14 T47D cell lines in which ERαY537S or ERαD538G replace one or both wild-type ERα genes. In 2-dimensional, and in quantitative anchorage-independent 3-dimensional cell culture, ERαY537S and ERαD538G cells exhibited estrogen-independent growth. A progestin further increased their already substantial proliferation in micromolar 4-hydroxytamoxifen and fulvestrant/ICI 182,780 (ICI). Our recently described ERα biomodulator, BHPI, which hyperactivates the unfolded protein response (UPR), completely blocked proliferation. In ERαY537S and ERαD538G cells, estrogen-ERα target genes were constitutively active and partially antiestrogen resistant. The UPR marker sp-XBP1 was constitutively activated in ERαY537S cells and further induced by progesterone in both cell lines. UPR-regulated genes associated with tamoxifen resistance, including the oncogenic chaperone BiP/GRP78, were upregulated. ICI displayed a greater than 2 fold reduction in its ability to induce ERαY537S and ERαD538G degradation. Progestins, UPR activation and perhaps reduced ICI-stimulated ERα degradation likely contribute to antiestrogen resistance seen in ERαY537S and ERαD538G cells.

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Section: Resultsmentioning

confidence: 99%

“…Weak activation of the UPR is protective in cancer and is associated with a poor prognosis, while extensive and sustained UPR activation by BHPI is toxic 21 22 24 29 . Since we cannot currently analyze protein and mRNA levels in cells from 3D cultures in soft agar, the UPR studies were carried out in standard 2D cell culture.…”

Section: Discussionmentioning

confidence: 99%

Antiestrogen Resistant Cell Lines Expressing Estrogen Receptor α Mutations Upregulate the Unfolded Protein Response and are Killed by BHPI

Mao

Livezey

Kim

et al. 2016

Sci Rep

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“…Importantly, BHPI , a recently described ERα biomodulator with anticancer activity, binds ERα at a different site than estrogens and induces a conformational change in ERα that leads to strong and sustained activation of the anticipatory UPR pathway [20]. While the mitogens E 2 , EGF and VEGF and the small molecule BHPI all activate the rapid anticipatory UPR pathway, DHT does not [21]. Instead, DHT activates the UPR after many hours [22].…”

Section: A Largely Common Pathway For Anticipatory Activation Of the Uprmentioning

confidence: 99%

Anticipatory UPR Activation: A Protective Pathway and Target in Cancer

Shapiro

Livezey

et al. 2016

Trends in Endocrinology & Metabolism

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The endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR), plays a key role in regulating intracellular protein homeostasis. The extensively studied reactive mode of UPR activation is characterized by unfolded protein, or other EnR stress, triggering UPR activation. Here we focus on the emerging anticipatory mode of UPR activation in which mitogenic steroid and peptide hormones and other effectors pre-activate the UPR and anticipate a future need for increased protein folding capacity. Mild UPR activation in breast cancer can be protective and contributes to antiestrogen resistance. Hyperactivation of the anticipatory UPR pathway in cancer cells with a small molecule converts it from cytoprotective to cytotoxic, highlighting its potential as a therapeutic target in estrogen receptor positive breast cancer.

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“…A possible explanation for the selective cytotoxicity of NDL is that the UPR is already elevated in tumor cells, whereas it is of much lower level in normal cells. Therefore, it is much easier to increase the UPR to a level of conversion in tumor cells as suggested by previous study [ 38 ]. The complex pharmacological nature of NDL was also displayed through its effects on genes of opposing activities.…”

Section: Discussionmentioning

confidence: 96%

Nam Dia long, a Vietnamese folk formula, induces apoptosis in MCF-7 cells through various mechanisms of action

Nguyen¹,

Ho-Huynh

2017

BMC Complement Altern Med

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BackgroundThe holistic approach of traditional medicine renders the identification of its mechanisms of action difficult. Microarray technology provides an efficient way to analyze the complex genome-wide gene expression of cells treated with mixtures of medicinal ingredients. We performed transcriptional profiling of MCF-7 cells treated with Nam Dia Long (NDL), a Vietnamese traditional formula, to explore the mechanism of action underlying the apoptosis inducing effect of this formula reported in a previous study.MethodsMCF-7 cells were treated with aqueous extracts of NDL at the IC50 concentration for 24, 36 and 48 h. Total RNAs at 24 h and 48 h were subsequently extracted, reverse transcribed and submitted to microarray expression profiling using the Human HT-12 v4.0 Expression Bead Chip (Illumina). Functional analyses were performed using the Database for Annotation, Visualization and Integrated Discovery and the Ingenuity Pathways Analysis. The expression level from selected genes at the three time points were assessed by quantitative real-time RT-PCR and Western blot.ResultsFifty-four and 601 genes were differentially expressed at 24 and 48 h of NDL treatment, respectively. Genes with altered expression at 24 h were mostly involved in cell responses to xenobiotic stress whereas genes differentially expressed at 48 h were related to endoplasmic reticulum stress, DNA damage and cell cycle control. Apoptosis of NDL treated MCF-7 cells resulted from a combination of different mechanisms including the intrinsic and extrinsic pathways, cell cycle arrest- and oxidative stress-related cell death.ConclusionNDL elicited a two-stage response in MCF-7 treated cells with apoptosis as the ultimate result. The various mechanisms inducing apoptosis reflected the complexity of the formula composition.Electronic supplementary materialThe online version of this article (10.1186/s12906-017-2027-2) contains supplementary material, which is available to authorized users.

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Interplay between steroid hormone activation of the unfolded protein response and nuclear receptor action

Cited by 16 publications

References 49 publications

Antiestrogen Resistant Cell Lines Expressing Estrogen Receptor α Mutations Upregulate the Unfolded Protein Response and are Killed by BHPI

Antiestrogen Resistant Cell Lines Expressing Estrogen Receptor α Mutations Upregulate the Unfolded Protein Response and are Killed by BHPI

Anticipatory UPR Activation: A Protective Pathway and Target in Cancer

Nam Dia long, a Vietnamese folk formula, induces apoptosis in MCF-7 cells through various mechanisms of action

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