Pre-malignant transformation by senescence evasion is prevented by the PERK and ATF6alpha branches of the Unfolded Protein Response

Cancer Lett. 2018 Dec 1:438:187-196. doi: 10.1016/j.canlet.2018.09.008. Epub 2018 Sep 11.

Abstract

The incidence of carcinomas highly increases with age. However, the initial steps of the age-related molecular carcinogenic processes remain poorly characterized. We previously showed that normal human epidermal keratinocytes spontaneously and systematically escape from senescence to give rise to preneoplastic emerging cells through a process called post-senescence neoplastic emergence (PSNE). To identify molecular pathways involved in the switch from senescence to pre-transformation, we performed Connectivity Map analyses and DAVID functional annotations followed by hierarchical clustering and multidimensional scaling of the gene expression signature of PSNE cells. We identified endoplasmic reticulum stress related pathways as key regulators of PSNE. Invalidation by RNA interference of the UPR sensors PERK, ATF6α, but not IRE1α, delayed the occurrence of senescence when performed in pre-senescent cells, and increased the PSNE frequency when performed in already senescent cells. Conversely, endoplasmic reticulum stress inducers applied to already senescent cells decreased the frequency of PSNE. In conclusion, these results indicate that the activation of the UPR could protect from the early carcinogenic steps by senescence evasion. This opens new avenues to explore therapeutics that could be useful in decreasing the age-associated tumor incidence.

Keywords: ATF6α; Endoplasmic reticulum; Normal human epidermal keratinocyte; PERK; Post-senescence neoplastic emergence; Senescence; Unfolded protein response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 6 / genetics*
  • Activating Transcription Factor 6 / metabolism
  • Aging / genetics
  • Aging / pathology
  • Cell Line
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Cellular Senescence / drug effects
  • Cellular Senescence / genetics
  • Endoplasmic Reticulum Stress / drug effects
  • Endoplasmic Reticulum Stress / genetics
  • Humans
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Pharmaceutical Preparations / administration & dosage
  • Pharmaceutical Preparations / classification
  • Precancerous Conditions / genetics
  • Precancerous Conditions / metabolism
  • Precancerous Conditions / pathology
  • RNA Interference
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Transcriptome*
  • Unfolded Protein Response / drug effects
  • Unfolded Protein Response / genetics*
  • eIF-2 Kinase / genetics*
  • eIF-2 Kinase / metabolism

Substances

  • ATF6 protein, human
  • Activating Transcription Factor 6
  • Pharmaceutical Preparations
  • EIF2AK3 protein, human
  • eIF-2 Kinase