Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state

Science. 2013 Jul 19;341(6143):1238303. doi: 10.1126/science.1238303.

Abstract

The ribosome is centrally situated to sense metabolic states, but whether its activity, in turn, coherently rewires transcriptional responses is unknown. Here, through integrated chemical-genetic analyses, we found that a dominant transcriptional effect of blocking protein translation in cancer cells was inactivation of heat shock factor 1 (HSF1), a multifaceted transcriptional regulator of the heat-shock response and many other cellular processes essential for anabolic metabolism, cellular proliferation, and tumorigenesis. These analyses linked translational flux to the regulation of HSF1 transcriptional activity and to the modulation of energy metabolism. Targeting this link with translation initiation inhibitors such as rocaglates deprived cancer cells of their energy and chaperone armamentarium and selectively impaired the proliferation of both malignant and premalignant cells with early-stage oncogenic lesions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / isolation & purification
  • Antineoplastic Agents / pharmacology
  • Benzofurans / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / biosynthesis*
  • Energy Metabolism / drug effects
  • Gene Expression Regulation, Neoplastic
  • Heat Shock Transcription Factors
  • High-Throughput Screening Assays
  • Humans
  • Mice
  • NIH 3T3 Cells
  • Neoplasm Transplantation
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Protein Biosynthesis / drug effects
  • Protein Biosynthesis / genetics
  • Protein Biosynthesis / physiology*
  • Ribosomes / drug effects
  • Ribosomes / metabolism*
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / biosynthesis*

Substances

  • Antineoplastic Agents
  • Benzofurans
  • DNA-Binding Proteins
  • HSF1 protein, human
  • Heat Shock Transcription Factors
  • Transcription Factors
  • rocaglamide

Associated data

  • GEO/GSE45853