Ouabain and digoxin activate the proteasome and the degradation of the erα in cells modeling primary and metastatic breast cancer

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number3840
Pages (from-to)1-26
Number of pages26
JournalCancers
Volume12
Issue number12
DOIs
Publication statusPublished - Dec 2020

Keywords

  • 17β-estradiol
  • Breast cancer
  • Digoxin
  • Estrogen receptor
  • Ouabain
  • Proteasome

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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