Abstract
The aging process is characterized by progressive accumulation of damaged biomolecules in the endoplasmic reticulum, as result of increased oxidative stress accompanying cellular senescence. In agreement, we hypothesized that WI-38 human cellular models of replicative senescence and stress-induced premature senescence (SIPS) induced by hydrogen peroxide (H2O2-SIPS) or copper sulfate (CuSO4-SIPS) would present endoplasmic reticulum chaperoning mechanisms impairment and unfolded protein response activation. Results show that in replicative senescence and CuSO4-SIPS, immunoglobulin binding protein, calnexin, protein disulfide isomerase, and ER oxireductin-1 levels adjust to restore proteostasis and inositol-requiring enzyme-1 (IRE1)-, activating transcription factor 6 (ATF6)-, and pancreatic ER kinase (PERK)-mediated unfolded protein response are activated. However, H2O2-SIPS does not exhibit IRE1 and ATF6 pathways activation but a PERK-mediated upregulation of CCAAT/enhancer-binding protein homologous protein, showing that CuSO4-SIPS mimics better the endoplasmic reticulum molecular events of replicative senescence than H2O2-SIPS. Moreover, unfolded protein response activation is required for both SIPS models induction, because PERK and IRE1 inhibitors decreased senescence-associated beta-galactosidase appearance. In CuSO4-SIPS, the decrease in senescence levels is associated with PERK-driven, but IRE1 independent, cell cycle arrest while in H2O2-SIPS cell proliferation is PERK independent. These results add a step further on the molecular mechanisms that regulate senescence induction; moreover, they validate CuSO4-SIPS model as a useful tool to study cellular stress responses during aging, hoping to postpone age-related health decline.
Highlights
The increase of elderly population raised interest in the mechanisms underlying the progressive functional decline and homeostasis imbalance that associate with aging
This study evaluates the levels of endoplasmic reticulum (ER) chaperoning system interveners and the activation of ER stress response during cellular senescence
Using replicative senescence (RS), H2O2- and CuSO4-stress-induced premature senescence (SIPS) human cellular models, it is shown that binding protein (BiP), calnexin, protein disulfide isomerase (PDI), and ER oxireductin-1 (Ero1) levels are adjusted to deal with senescence-associated imbalance in prosteostasis
Summary
The increase of elderly population raised interest in the mechanisms underlying the progressive functional decline and homeostasis imbalance that associate with aging. This complex response is mediated by three ER transmembrane sensors: pancreatic ER kinase like ER kinase (PERK), activating transcription factor-6 (ATF6), and inositol-requiring enzyme-1 (IRE1) These UPR pathways limit ER abnormal protein load and alleviate ER stress by attenuating protein translation [8], upregulating ER chaperones [9], and degrading misfolded proteins in the proteasome by an ER-associated degradation process [10]. If these protective cellular responses do not restore normal ER functioning, apoptosis is activated [7,11]. Cells in RS exhibit dramatic changes in morphology, gene expression and organelle structure, mass, and function when compared with proliferating cells (for a review see Ref. [18])
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