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.
Department of Endocrinology and Medicine, University of Genoa, Genoa, Italy.
Barbara
B
Salani
Sara
S
Maffioli
Meriem
M
Hamoudane
Alessia
A
Parodi
Silvia
S
Ravera
Mario
M
Passalacqua
Angela
A
Alama
Mohamed
M
Nhiri
Renzo
R
Cordera
Davide
D
Maggi
D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051242:Caveolin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008687:Metformin / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
C495540:CAV1 protein, human; D051242:Caveolin 1; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007004:Hypoglycemic Agents; D034741:RNA, Small Interfering; D007334:Insulin-Like Growth Factor I; D008687:Metformin; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt