Caveolin-1 is essential for metformin inhibitory effect on IGF1 action in non-small-cell lung cancer cells

Barbara Salani, Sara Maffioli, Meriem Hamoudane, Alessia Parodi, Silvia Ravera, Mario Passalacqua, Angela Alama, Mohamed Nhiri, Renzo Cordera, Davide Maggi

Research output: Contribution to journalArticle

Abstract

Metformin causes an AMP/ATP ratio increase and AMP-activated protein kinase (AMPK) activation. Since caveolin-1 (Cav-1) plays a role in AMPK activation and energy balance, we investigated whether Cav-1 could participate in metformin's inhibitory effect on IGF1 signaling. The effect of metformin was studied in two non-small-cell lung cancer (NSCLC) cell lines, Calu-1 and Calu-6, expressing higher and lower amounts of Cav-1, respectively. In Calu-1, but not in Calu-6 cells, metformin reduced phosphorylation of type 1 insulin-like growth factor receptor (IGF-IR) substrates Akt and Forkhead transcription factor 3a (FOXO3a), inhibited IGF1-dependent FOXO3a nuclear exit, and decreased IGF1-dependent cell proliferation. Here, we show that sensitivity of NSCLC cells to metformin was dependent on Cav-1 expression and that metformin required Cav-1 to induce AMPK phosphorylation and AMP/ATP ratio increase. Cav-1 silencing in Calu-1 and overexpression in Calu-6 reduced and improved, respectively, the inhibitory effect of metformin on IGF1-dependent Akt phosphorylation. Prolonged metformin treatment in Calu-6 cells induced a dose-dependent expression increase of Cav-1 and OCT1, a metformin transporter. Cav-1 and OCT1 expression was associated with the antiproliferative effect of metformin in Calu-6 cells (IC50=18 mM). In summary, these data suggest that Cav-1 is required for metformin action in NSCLC cells.

Original languageEnglish
Pages (from-to)788-798
Number of pages11
JournalFASEB Journal
Volume26
Issue number2
DOIs
Publication statusPublished - Feb 2012

Keywords

  • AKT
  • FOXO3a
  • NSCLC
  • OCT1

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

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    Salani, B., Maffioli, S., Hamoudane, M., Parodi, A., Ravera, S., Passalacqua, M., Alama, A., Nhiri, M., Cordera, R., & Maggi, D. (2012). Caveolin-1 is essential for metformin inhibitory effect on IGF1 action in non-small-cell lung cancer cells. FASEB Journal, 26(2), 788-798. https://doi.org/10.1096/fj.11-192088