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J Biol Chem. 2014 Jul 18;289(29):20102-19. doi: 10.1074/jbc.M114.551069. Epub 2014 Jun 4.

The nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) promotes oncogene-induced cellular senescence through repression of endoplasmic reticulum stress.

Author information

  • 1From the Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802 and.
  • 2the Laboratory of Metabolism, NCI, National Institutes of Health, Bethesda, Maryland 20892.
  • 3From the Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802 and jmp21@psu.edu.

Abstract

Endoplasmic reticulum (ER) stress and ER stress-associated unfolded protein response (UPR) can promote cancer cell survival, but it remains unclear whether they can influence oncogene-induced senescence. The present study examined the role of ER stress in senescence using oncogene-dependent models. Increased ER stress attenuated senescence in part by up-regulating phosphorylated protein kinase B (p-AKT) and decreasing phosphorylated extracellular signal-regulated kinase (p-ERK). A positive feed forward loop between p-AKT, ER stress, and UPR was discovered whereby a transient increase of ER stress caused reduced senescence and promotion of tumorigenesis. Decreased ER stress was further correlated with increased senescence in both mouse and human tumors. Interestingly, H-RAS-expressing Pparβ/δ null cells and tumors having increased cell proliferation exhibited enhanced ER stress, decreased cellular senescence, and/or enhanced tumorigenicity. Collectively, these results demonstrate a new role for ER stress and UPR that attenuates H-RAS-induced senescence and suggest that PPARβ/δ can repress this oncogene-induced ER stress to promote senescence in accordance with its role as a tumor modifier that suppresses carcinogenesis.

© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

KEYWORDS:

Cancer; Cancer Biology; Cancer Therapy; H-RAS-induced Senescence; Keratinocyte; Oncogene-induced Endoplasmic Reticulum Stress; Peroxisome Proliferator-activated Receptor β/δ; Tumor Suppressor Gene

PMID:
24898257
[PubMed - indexed for MEDLINE]
PMCID:
PMC4106326
[Available on 2015/7/18]

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