Deep Proteomics of Breast Cancer Cells Reveals that Metformin Rewires Signaling Networks Away from a Pro-growth State

Francesca Sacco, Alessandra Silvestri, Daniela Posca, Stefano Pirrò, Pier Federico Gherardini, Luisa Castagnoli, Matthias Mann, Gianni Cesareni

Research output: Contribution to journalArticle

Abstract

Summary Metformin is the most frequently prescribed drug for type 2 diabetes. In addition to its hypoglycemic effects, metformin also lowers cancer incidence. This anti-cancer activity is incompletely understood. Here, we profiled the metformin-dependent changes in the proteome and phosphoproteome of breast cancer cells using high-resolution mass spectrometry. In total, we quantified changes of 7,875 proteins and 15,813 phosphosites after metformin changes. To interpret these datasets, we developed a generally applicable strategy that overlays metformin-dependent changes in the proteome and phosphoproteome onto a literature-derived network. This approach suggested that metformin treatment makes cancer cells more sensitive to apoptotic stimuli and less sensitive to pro-growth stimuli. These hypotheses were tested in vivo; as a proof-of-principle, we demonstrated that metformin inhibits the p70S6K-rpS6 axis in a PP2A-phosphatase dependent manner. In conclusion, analysis of deep proteomics reveals both detailed and global mechanisms that contribute to the anti-cancer activity of metformin.

Original languageEnglish
Pages (from-to)159-171
Number of pages13
JournalCell Systems
Volume2
Issue number3
DOIs
Publication statusPublished - Mar 23 2016

ASJC Scopus subject areas

  • Cell Biology
  • Histology
  • Pathology and Forensic Medicine

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    Sacco, F., Silvestri, A., Posca, D., Pirrò, S., Gherardini, P. F., Castagnoli, L., Mann, M., & Cesareni, G. (2016). Deep Proteomics of Breast Cancer Cells Reveals that Metformin Rewires Signaling Networks Away from a Pro-growth State. Cell Systems, 2(3), 159-171. https://doi.org/10.1016/j.cels.2016.02.005