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

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 (IC 50 =18 mM). In summary, these data suggest that Cav‐1 is required for metformin action in NSCLC cells.—Salani, B., Maffioli, S., Hamoudane, M., Parodi, A., Ravera, S., Passalacqua, M., Alama, A., Nhiri, M., Cordera, R., Maggi, D. Caveolin‐1 is essential for metformin inhibitory effect on IGF1 action in non‐small‐cell lung cancer cells. FASEB J. 26, 788–798 (2012). www.fasebj.org