scholarly journals Unexpected Impact of a Hepatitis C Virus Inhibitor on 17β-Estradiol Signaling in Breast Cancer

2020 ◽  
Vol 21 (10) ◽  
pp. 3418 ◽  
Author(s):  
Stefania Bartoloni ◽  
Stefano Leone ◽  
Filippo Acconcia
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Drug Repurposing ◽  
Estrogen Receptor Α ◽  
Physiological Processes ◽  
17Β Estradiol ◽  
Approved Drugs ◽  
First Time

17β-Estradiol (E2) controls diverse physiological processes, including cell proliferation, through its binding to estrogen receptor α (ERα). E2:ERα signaling depends on both the receptor subcellular localization (e.g., nucleus, plasma membrane) and intracellular ERα abundance. Indeed, the control of ERα levels is necessary for the effects of E2, and E2 itself induces ERα degradation and cell proliferation in parallel. Thus, the modulation of intracellular ERα levels is a critical parameter for E2-induced cell proliferation. Therefore, we used this parameter as a bait to identify compounds that influence ERα levels and E2-dependent proliferation in breast cancer (BC) cells from a library of Food and Drug Administration (FDA)-approved drugs. We found that telaprevir (Tel) reduces ERα levels and inhibits BC cell proliferation. Tel is an inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease, but its effect on E2:ERα signaling has not been investigated. Here, for the first time, we analyzed the effects of Tel on intracellular ERα levels and E2:ERα signaling to cell proliferation in different ERα-expressing BC cell lines. Overall, our findings demonstrate that Tel reduces intracellular ERα levels, deregulates E2:ERα signaling and inhibits E2-induced proliferation in BC cells and suggest the potential drug repurposing of Tel for the treatment of BC.

scholarly journals A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds against ERα Expressing Breast Cancer Cells

2021 ◽  
Vol 22 (6) ◽  
pp. 2915
Author(s):  
Manuela Cipolletti ◽  
Stefania Bartoloni ◽  
Claudia Busonero ◽  
Martina Parente ◽  
Stefano Leone ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Bioactive Compounds ◽  
Estrogenic Activity ◽  
Estrogen Receptor Α ◽  
Breast Cancers ◽  
Cellular Models ◽  
Cancer Models ◽  
17Β Estradiol ◽  
Approved Drugs ◽  
Anti Fungal

17β-estradiol (E2) exerts its physiological effects through the estrogen receptor α (i.e., ERα). The E2:ERα signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ERα positive (ERα+) breast cancers (BCs). The presence of ERα at the BC diagnosis drives their therapeutic treatment with the endocrine therapy (ET), which restrains BC progression. Nonetheless, many patients develop metastatic BCs (MBC) for which a treatment is not available. Consequently, the actual challenge is to complement the drugs available to fight ERα+ primary and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ERα signaling to cell proliferation in cellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo) and fenticonazole (Fenti) induce ERα degradation and prevent ERα transcriptional signaling and proliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo and Fenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with the CDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as “anti-estrogens”-like drugs. Remarkably, the present “anti-estrogen” discovery platform represents a valuable method to rapidly identify bioactive compounds with anti-estrogenic activity.

scholarly journals A functional drug re-purposing screening identifies carfilzomib as a drug preventing 17β-estradiol: ERα signaling and cell proliferation in breast cancer cells

2017 ◽  
Author(s):  
Claudia Busonero ◽  
Stefano Leone ◽  
Cinzia Klemm ◽  
Filippo Acconcia
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cell Model ◽  
Acquired Resistance ◽  
Estrogen Receptor Α ◽  
Attractive Alternative ◽  
Novel Drugs ◽  
A Cell ◽  
17Β Estradiol ◽  
Cell Model System

AbstractMost cases of breast cancer (BC) are estrogen receptor α-positive (ERα+) at diagnosis. The presence of ERα drives the therapeutic approach for this disease, which often consists of endocrine therapy (ET). 4OH-Tamoxifen and faslodex (i.e., fulvestrant - ICI182,780) are two ETs that render tumor cells insensitive to 17β-estradiol (E2)-dependent proliferative stimuli and prevent BC progression. However, ET has limitations and serious failures in different tissues and organs. Thus, there is an urgent need to identify novel drugs to fight BC in the clinic. Re-positioning of old drugs for new clinical purposes is an attractive alternative for drug discovery. For this analysis, we focused on the modulation of intracellular ERα levels in BC cells as target for the screening of about 900 Food and Drug Administration (FDA) approved compounds that would hinder E2:ERα signaling and inhibit BC cell proliferation. We found that carfilzomib induces ERα degradation and prevents E2 signaling and cell proliferation in two ERα+ BC cell lines. Remarkably, the analysis of carfilzomib effects on a cell model system with an acquired resistance to 4OH-tamoxifen revealed that this drug has an antiproliferative effect superior to faslodex in BC cells. Therefore, our results identify carfilzomib as a drug preventing E2:ERα signaling and cell proliferation in BC cells and suggest its possible re-position for the treatment of ERα+ BC as well as for those diseases that have acquired resistance to 4OH-tamoxifen.

scholarly journals PARP7 and Mono-ADP-Ribosylation Negatively Regulate Estrogen Receptor α Signaling in Human Breast Cancer Cells

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 623
Author(s):  
Marit Rasmussen ◽  
Susanna Tan ◽  
Venkata S. Somisetty ◽  
David Hutin ◽  
Ninni Elise Olafsen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Protein Modification ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
Transactivation Domain ◽  
Adp Ribosylation ◽  
Protein Levels ◽  
17Β Estradiol ◽  
Mcf 7

ADP-ribosylation is a post-translational protein modification catalyzed by a family of proteins known as poly-ADP-ribose polymerases. PARP7 (TIPARP; ARTD14) is a mono-ADP-ribosyltransferase involved in several cellular processes, including responses to hypoxia, innate immunity and regulation of nuclear receptors. Since previous studies suggested that PARP7 was regulated by 17β-estradiol, we investigated whether PARP7 regulates estrogen receptor α signaling. We confirmed the 17β-estradiol-dependent increases of PARP7 mRNA and protein levels in MCF-7 cells, and observed recruitment of estrogen receptor α to the promoter of PARP7. Overexpression of PARP7 decreased ligand-dependent estrogen receptor α signaling, while treatment of PARP7 knockout MCF-7 cells with 17β-estradiol resulted in increased expression of and recruitment to estrogen receptor α target genes, in addition to increased proliferation. Co-immunoprecipitation assays revealed that PARP7 mono-ADP-ribosylated estrogen receptor α, and mass spectrometry mapped the modified peptides to the receptor’s ligand-independent transactivation domain. Co-immunoprecipitation with truncated estrogen receptor α variants identified that the hinge region of the receptor is required for PARP7-dependent mono-ADP-ribosylation. These results imply that PARP7-mediated mono-ADP-ribosylation may play an important role in estrogen receptor positive breast cancer.

scholarly journals Silymarin Inhibits In Vitro T-Cell Proliferation and Cytokine Production in Hepatitis C Virus Infection

2010 ◽  
Vol 138 (2) ◽  
pp. 671-681.e2 ◽  
Author(s):  
Chihiro Morishima ◽  
Margaret C. Shuhart ◽  
Chia C. Wang ◽  
Denise M. Paschal ◽  
Minjun C. Apodaca ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Virus Infection ◽  
Cytokine Production ◽  
T Cell Proliferation ◽  
Hepatitis C Virus Infection

Winners of the Nobel Prize in Medicine in 2020

2021 ◽  
pp. 59-63
Author(s):  
Oksana Aleksandrovna Rybachok
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Nobel Prize ◽  
The Body ◽  
Coronavirus Infection ◽  
First Time ◽  
Selection Of

Despite the height of the coronavirus infection, the Nobel Prize in Medicine was awarded in Stockholm in October 2020. This event was held online for the first time and was not accompanied by the traditional honoring of the laureates. In his will, Alfred Nobel entrusted the selection of the winner in this nomination to the Karolinska Medical and Surgical University of Stockholm, and the first award in this nomination took place in 1901. Since then, this event has been held 110 times, and 216 scientists have become laureates of the prize in the field of physiology and medicine, since the nominees are often not just one, but a group of researchers. This happened in 2020 - for research in the field of studying the hepatitis C virus, three scientists received the most prestigious award: the British Michael Houghton and the Americans Harvey Alter and Charles Rice. Due to the results of the research, which these three people conducted separately from each other, for the first time it became possible to completely eliminate the virus from the body.

scholarly journals A Novel Antiviral Treatment of Hepatitis C Virus Reactivation in a Breast Cancer Patient Undergoing Chemotherapy

2017 ◽  
Vol 130 (16) ◽  
pp. 2015-2016 ◽  
Author(s):  
Yu-Tuan Wu ◽  
Zhou Xu ◽  
Hao-Ran Chen ◽  
Bilal Arshad ◽  
Hong-Yuan Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Cancer Patient ◽  
Breast Cancer Patient ◽  
Antiviral Treatment ◽  
Virus Reactivation

scholarly journals Expression of the Novel Hepatitis C Virus Core+1/ARF Protein in the Context of JFH1-Based Replicons

2015 ◽  
Vol 89 (9) ◽  
pp. 5164-5170 ◽  
Author(s):  
Ioly Kotta-Loizou ◽  
Ioannis Karakasiliotis ◽  
Niki Vassilaki ◽  
Panagiotis Sakellariou ◽  
Ralf Bartenschlager ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Core Gene ◽  
Open Reading Frame ◽  
The Novel ◽  
Reading Frame ◽  
The Core ◽  
Virus Core ◽  
First Time ◽  
Arf Protein

Hepatitis C virus contains a second open reading frame within the core gene, designated core+1/ARF. Here we demonstrate for the first time expression of core+1/ARF protein in the context of a bicistronic JFH1-based replicon and report the production of two isoforms, core+1/L (long) and core+1/S (short), with different kinetics.

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