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

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

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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Adenoma / genetics
  • Adenoma / metabolism
  • Adenoma / pathology
  • Animals
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cells, Cultured
  • Cellular Senescence / genetics*
  • Cellular Senescence / physiology*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • DNA-Binding Proteins / genetics
  • Endoplasmic Reticulum Chaperone BiP
  • Endoplasmic Reticulum Stress*
  • Gene Expression
  • Gene Knockdown Techniques
  • Genes, p53
  • Genes, ras*
  • Heat-Shock Proteins / genetics
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / metabolism
  • Mice
  • Models, Biological
  • PPAR delta / deficiency
  • PPAR delta / genetics
  • PPAR delta / metabolism*
  • PPAR-beta / deficiency
  • PPAR-beta / genetics
  • PPAR-beta / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Small Interfering / genetics
  • Regulatory Factor X Transcription Factors
  • Signal Transduction
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / genetics
  • Unfolded Protein Response

Substances

  • ATF4 protein, human
  • Atf4 protein, mouse
  • DNA-Binding Proteins
  • Endoplasmic Reticulum Chaperone BiP
  • Heat-Shock Proteins
  • PPAR delta
  • PPAR-beta
  • RNA, Small Interfering
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • Activating Transcription Factor 4
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases