Ouabain and Digoxin Activate the Proteasome and the Degradation of the ERα in Cells Modeling Primary and Metastatic Breast Cancer

Busonero, Claudia; Leone, Stefano; Bianchi, Fabrizio; Maspero, Elena; Fiocchetti, Marco; Palumbo, Orazio; Cipolletti, Manuela; Bartoloni, Stefania; Acconcia, Filippo

doi:10.3390/cancers12123840

Cited by 15 publications

(49 citation statements)

References 63 publications

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“…For example, inhibition of polyubiquitination of ERα leads to an increase in the stability of the receptor [105]. Moreover, a recent report describes the ability of cardiac glycosides Ouabain and Digoxin to degrade ERα, potentially via activation of the proteasomal system, with subsequent inhibition of estrogen signaling, cell cycle blockade and apoptosis of primary and metastatic breast cancer cells [106]. The complex interaction between ERs and the UPS has been reviewed elsewhere [104].…”

Section: Ligand-independent Activation Of Erαmentioning

confidence: 99%

Nexus between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer

Khatpe

Adebayo

Herodotou

et al. 2021

Cancers

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Signaling from estrogen receptor alpha (ERα) and its ligand estradiol (E2) is critical for growth of ≈70% of breast cancers. Therefore, several drugs that inhibit ERα functions have been in clinical use for decades and new classes of anti-estrogens are continuously being developed. Although a significant number of ERα+ breast cancers respond to anti-estrogen therapy, ≈30% of these breast cancers recur, sometimes even after 20 years of initial diagnosis. Mechanism of resistance to anti-estrogens is one of the intensely studied disciplines in breast cancer. Several mechanisms have been proposed including mutations in ESR1, crosstalk between growth factor and ERα signaling, and interplay between cell cycle machinery and ERα signaling. ESR1 mutations as well as crosstalk with other signaling networks lead to ligand independent activation of ERα thus rendering anti-estrogens ineffective, particularly when treatment involved anti-estrogens that do not degrade ERα. As a result of these studies, several therapies that combine anti-estrogens that degrade ERα with PI3K/AKT/mTOR inhibitors targeting growth factor signaling or CDK4/6 inhibitors targeting cell cycle machinery are used clinically to treat recurrent ERα+ breast cancers. In this review, we discuss the nexus between ERα-PI3K/AKT/mTOR pathways and how understanding of this nexus has helped to develop combination therapies.

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Section: Ligand-independent Activation Of Erαmentioning

confidence: 99%

Nexus between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer

Khatpe

Adebayo

Herodotou

et al. 2021

Cancers

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“…In turn, real-time growth curve analysis was next conducted in MCF-7 cells [20,30]. Figure 7c,d show that E2 promotes MCF-7 cell proliferation, while Clo and Fenti treatment significantly reduces the basal and the E2-induced proliferation of MCF-7 cells.…”

Section: Clotrimazole and Fenticonazole Administration Prevents E2-induced Cell Proliferationmentioning

confidence: 99%

“…For growth curves and drug synergy studies the xCELLigence DP system ACEA Biosciences, Inc. (San Diego, CA, USA) Multi-E-Plate station was used to measure the time-dependent response to the indicated drugs by real-time cell analysis (RTCA), as previously reported [20,29,30]. Briefly, the number of cells (i.e., normalized cell index) is directly proportional to the measured electric impedance of the cells on the well surface.…”

Section: Cell Proliferation and Cell Cycle Assaysmentioning

confidence: 99%

“…Tumor spheroid formation was performed as previously reported [30]. Briefly, Y537S cells were seeded (10,000 cells/well) in ultra-low attachment surface 24-well-plates (Sigma-Aldrich) with 1 mL/well in growing condition for 48 h. Next, using an optical microscope, pictures had been taken for each well in untreated conditions (i.e., time 0).…”

Section: Tumor Spheroid Formationmentioning

confidence: 99%

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

Cipolletti

Bartoloni

Busonero

et al. 2021

IJMS

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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.

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“…The structure of ouabain has a steroid core with a fivemembered unsaturated butyrolactone ring at position 17 and a rhamnose residue at position 3 (Figure 1A) (7). Increasing literatures have demonstrated the antiproliferative effects of ouabain on various cancer cells including breast cancer (8), lung cancer (9), prostate cancer (10), colon cancer (11) and leukemia (12). Although the detailed mechanisms have not been fully elucidated, ouabain has been shown to exert antitumor effects manifested in the activation of various modes of cell death, including apoptosis, autophagy and immunogenic cell death (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Cardiac Glycoside Ouabain Exerts Anticancer Activity via Downregulation of STAT3

Jiang

Chen

et al. 2021

Front. Oncol.

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Cardiac glycosides are plant-derived steroid-like compounds which have been used for the treatment of cardiovascular diseases. Ouabain, a cardiotonic steroid and specific Na+/K+-ATPase inhibitor, has been rediscovered for its potential use in the treatment of cancer. However, the cellular targets and anticancer mechanism of ouabain in various cancers remain largely unexplored. In this study, we confirmed the cytotoxic effects of ouabain on several cancer cell lines. Further examination revealed the increase of apoptosis, intracellular ROS generation and DNA double-strand breaks induced by ouabain treatment. Besides, ouabain effectively suppressed STAT3 expression as well as phosphorylation in addition to block STAT3-mediated transcription and downstream target proteins. Interestingly, these inhibitory activities seemed to be independent of the Na+/K+-ATPase. Furthermore, we found that ouabain inhibited protein synthesis through regulation of the eukaryotic initiation factor 4E (eIF4E) and eIF4E binding protein 1 (4EBP1). Taken together, our study provided a novel molecular insight of anticancer activities of ouabain in human cancer cells, which could raise the hope of using cardiac glycosides for cancer therapeutics more rational.

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Ouabain and Digoxin Activate the Proteasome and the Degradation of the ERα in Cells Modeling Primary and Metastatic Breast Cancer

Cited by 15 publications

References 63 publications

Nexus between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer

Nexus between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer

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

Cardiac Glycoside Ouabain Exerts Anticancer Activity via Downregulation of STAT3

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