TY - JOUR
T1 - Ouabain and digoxin activate the proteasome and the degradation of the erα in cells modeling primary and metastatic breast cancer
AU - Busonero, Claudia
AU - Leone, Stefano
AU - Bianchi, Fabrizio
AU - Maspero, Elena
AU - Fiocchetti, Marco
AU - Palumbo, Orazio
AU - Cipolletti, Manuela
AU - Bartoloni, Stefania
AU - Acconcia, Filippo
N1 - Funding Information:
Funding: The research leading to these results has received funding from AIRC under IG 2018–ID. 21325 project and under MFAG–ID. 12756–P.I. Acconcia Filippo. This study was also supported by grants from Ateneo Roma Tre and Fondo di finanziamento per le attività base di ricerca (FFABR) to F.A. The Grant of Excellence Departments, MIUR (ARTICOLO 1, COMMI 314–337 LEGGE 232/2016) to Department of Science, University Roma TRE is also gratefully acknowledged.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2020/12
Y1 - 2020/12
N2 - Estrogen receptor α expressing breast cancers (BC) are classically treated with endocrine therapy. Prolonged endocrine therapy often results in a metastatic disease (MBC), for which a standardized effective therapy is still lacking. Thus, new drugs are required for primary and metastatic BC treatment. Here, we report that the Food and Drug Administration (FDA)-approved drugs, ouabain and digoxin, induce ERα degradation and prevent proliferation in cells modeling primary and metastatic BC. Ouabain and digoxin activate the cellular proteasome, instigating ERα degradation, which causes the inhibition of 17β-estradiol signaling, induces the cell cycle blockade in the G2 phase, and triggers apoptosis. Remarkably, these effects are independent of the inhibition of the Na/K pump. The antiproliferative effects of ouabain and digoxin occur also in diverse cancer models (i.e., tumor spheroids and xenografts). Additionally, gene profiling analysis reveals that these drugs downregulate the expression of genes related to endocrine therapy resistance. Therefore, ouabain and digoxin behave as ‘anti-estrogen’-like drugs, and are appealing candidates for the treatment of primary and metastatic BCs.
AB - Estrogen receptor α expressing breast cancers (BC) are classically treated with endocrine therapy. Prolonged endocrine therapy often results in a metastatic disease (MBC), for which a standardized effective therapy is still lacking. Thus, new drugs are required for primary and metastatic BC treatment. Here, we report that the Food and Drug Administration (FDA)-approved drugs, ouabain and digoxin, induce ERα degradation and prevent proliferation in cells modeling primary and metastatic BC. Ouabain and digoxin activate the cellular proteasome, instigating ERα degradation, which causes the inhibition of 17β-estradiol signaling, induces the cell cycle blockade in the G2 phase, and triggers apoptosis. Remarkably, these effects are independent of the inhibition of the Na/K pump. The antiproliferative effects of ouabain and digoxin occur also in diverse cancer models (i.e., tumor spheroids and xenografts). Additionally, gene profiling analysis reveals that these drugs downregulate the expression of genes related to endocrine therapy resistance. Therefore, ouabain and digoxin behave as ‘anti-estrogen’-like drugs, and are appealing candidates for the treatment of primary and metastatic BCs.
KW - 17β-estradiol
KW - Breast cancer
KW - Digoxin
KW - Estrogen receptor
KW - Ouabain
KW - Proteasome
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U2 - 10.3390/cancers12123840
DO - 10.3390/cancers12123840
M3 - Article
AN - SCOPUS:85098263778
VL - 12
SP - 1
EP - 26
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 12
M1 - 3840
ER -