Induction of Cellular Senescence by Secretory Phospholipase A2 in Human Dermal Fibroblasts through an ROS-Mediated p53 Pathway

Abstract

Secretory phospholipase A(2) (sPLA(2)) is involved in various cellular physiological and pathological responses, especially in inflammatory responses. Accumulating evidence suggests that inflammation is an underlying basis for the molecular alterations that link aging and age-related pathological processes. However, the involvement of sPLA(2) in cellular senescence is not clear. In this study, we found that sPLA(2) treatment induces cellular senescence in human dermal fibroblasts (HDFs), as confirmed by increases in senescence-associated beta-galactosidase activity, changes in cell morphology, and upregulation of p53/p21 protein levels. sPLA(2)-induced senescence was observed in p16-knockdown HDFs and p16-null mouse fibroblasts, but not in p53-knockdown HDFs and p53-null mouse fibroblasts. Treatment with sPLA(2) increases reactive oxygen species (ROS) production, and an antioxidant, N-acetylcysteine, inhibits sPLA(2)-induced cellular senescence. These results suggest that sPLA(2) has a role in cellular senescence in HDFs during inflammatory response by promoting ROS-dependent p53 activation and might therefore contribute to inflammatory disorders associated with aging.

Involvement of IGF binding protein 5 in prostaglandin E2-induced cellular senescence in human fibroblasts

“…Our previous study identified secretory PLA 2 as playing an important role in regulating cellular senescence in HDFs through an ROS dependent p53 signaling pathway (Kim et al 2009). sPLA 2 s produce arachidonic acid (AA) and lysophospholipids by hydrolyzing membrane phospholipids, and AA is converted into prostaglandins and leukotrienes by cyclooxygenases (COXs) and lipoxygenases (LOXs), respectively (Dennis 1994).…”

“…However, some indirect evidence suggests that PGE 2 may associate with the induction of cellular senescence. In a previous study, secretory PLA 2 was found to induce fibroblast senescence through a p53 signaling pathway (Kim et al 2009). COX-2, an inducible enzyme in the prostaglandin biosynthesis pathway, is up-regulated in fibroblasts during replicative senescence (Han et al 2004;Yoon et al 2004;Zdanov et al 2007).…”

“…Since a previous study showed that sPLA 2 induces cellular senescence in HDFs (Kim et al 2009), the effects of PGE 2 on the regulation of cellular senescence were investigated. PGE 2 is one of major prostanoids, produced by cyclooxygenase from arachidonic acid, which is hydrolyzed from membrane phospholipids by PLA 2 .…”

PLA2R1 Mediates Tumor Suppression by Activating JAK2

“…It belongs to the mannose receptor family and binds several secreted phospholipases A2 (sPLA2s), different types of collagens, and carbohydrates. Some secreted phospholipase A2 has also been shown to induce a premature senescence in normal human fibroblasts (11). Nevertheless, the physiological consequences of these ligands and their binding to receptors remain unclear.…”

Nouveaux rôles physiopathologiques pour le récepteur PLA2R1 dans le cancer et la glomérulonéphrite extramembraneuse

“…L'effet pro-sénescent de PLA2R1 dépend de la production de radicaux oxygénés (reactive oxygen species, ROS), de l'induction de dommages à l'ADN et de l'activation du gène suppresseur de tumeurs p53 [19]. Les sPLA2 IB et IIA contrôlent également la sénescence cellulaire [19,21,42,43]. Néanmoins, la contribution de PLA2R1 dans leurs effets n'est pas clairement établie [19].…”