P2Y11 receptor is a critical regulator of extracellular ATP-mediated premature senescence in lung fibroblasts: Implications of ER-Ca+2 release/mitochondrial ROS production signaling pathway

Cellular senescence is characterized by the cessation of cell division.Numerous stressful stimuli, such as UV light exposure and oxidative stress, can hasten senescence 1.Nucleotides and their purinergic receptors (P2R) have been reported to play a central role in many different cellular signaling processes.In a recent publication in J. Biol.Chem, Volonte et al. 2, showed that oxidative stress mediated ATP release and induced human lung fibroblast senescence.Extracellular ATP or oxidative stress-mediated premature senescence was inhibited by pharmacological antagonism of the P2Y11 receptor (P2R 11 R) with a selective antagonist, NF-157; furthermore, the P2Y 11 R activation with NF-546 (a selective P2Y 11 R agonist) induced cellular senescence.In addition, P2Y 11 R activation by NF-546 or ATP evoked endoplasmic reticulum (ER) Ca +2 release, which subsequently entered mitochondria and induced reactive oxygen species (ROS) generation.This in turn prompted premature senescence of lung fibroblasts.Finally, the authors demonstrated that ATPstimulated lung fibroblasts secreted amphiregulin, which enhanced the growth of triple-negative breast cancer cells.