Extracellular ATP regulates FoxO transcription factors and cell cycle progression in MCF-7 cells

SCODELARO BILBAO, PAOLA GABRIELA; BOLAND, RICARDO

Mendoza

Congreso; XLVIII Reunión de la Sociedad Argentina de Investigación Bioquímica y Biología Molecular; 2012

Sociedad Argentina de Investigación Bioquímica y Biología Molecular

Forkhead box-O (FoxO) transcription factors regulate the expression of genes involved in DNA damage repair, apoptosis and cell cycle. Thus, they play an important role in tumour suppression. Released nucleotides can regulate intracellular signaling pathways through membrane-bound purinergic receptors, to promote or prevent malignant cell transformation. We studied the role of extracellular ATP in the modulation of FoxO transcription factors and of cell cycle progression in MCF-7 breast cancer cells. Western blot analysis showed that ATP induced the phosphorylation of FoxO1/3a, and also reduced the expression of FoxO1. The phosphatidilinositol 3 kinase (PI3K) inhibitor Ly294002 and siRNA against the serine/threonine kinase Akt showed that these effects are mediated by the PI3K/Akt signaling pathway. In addition, ATP increased the expression of the cyclins D1 and D3 and diminished the inhibitory proteins p21Cip1 and p27Kip1, in a PI3K/Akt dependent manner as revealed by the use of Ly294002 and siRNA against Akt. Flow cytometry analysis showed that ATP increases the number of cells in the S phase of cell cycle, effect that was significantly reduced in the presence of Ly294002 and bortezomib, a proteasome inhibitor. Our results suggest that extracellular ATP can play a pivotal role in breast cancer cell proliferation inducing cell cycle progression through the PI3K/Akt/FoxO pathway.