Ligand-activated PPAR delta inhibits UVB-induced senescence of human keratinocytes via PTEN-mediated inhibition off superoxide production

Abstract

UV radiation-mediated photodamage to the skin has been implicated in premature aging and photoaging-related skin cancer and melanoma. Little is known about the cellular events that underlie premature senescence, or how to impede these events. In the present study we demonstrate that PPAR delta (peroxisome-proliferator-activated receptor delta) regulates UVB-induced premature senescence of normal keratinocytes. Activation of PPAR delta by GW501516, a specific ligand of PPAR delta, significantly attenuated UVB-mediated generation of ROS (reactive oxygen species) and suppressed senescence of human keratinocytes. Ligand-activated PPAR delta up-regulated the expression of PTEN (phosphatase and tensin homologue deleted on chromosome 10) and suppressed the PI3K (phosphatidylinositol 3-kinase)/Akt pathway. Concomitantly, translocation of Rac 1 to the plasma membrane, which leads to the activation of NADPH oxidases and generation of ROS, was significantly attenuated. siRNA (small interfering RNA)-mediated knockdown of PTEN abrogated the effects of PPAR delta on cellular senescence, on PI3K/Akt/Rac 1 signalling and on generation of ROS in keratinocytes exposed to UVB. Finally, when HR-1 hairless mice were treated with GW501516 before exposure to UVB, the number of senescent cells in the skin was significantly reduced. Thus ligand-activated PPAR delta confers resistance to UVB-induced cellular senescence by up-regulating PTEN and thereby modulating PI3K/Akt/Rac 1 signalling to reduce ROS generation in keratinocytes.