Upregulation of heat shock proteins and the promotion of damage-associated molecular pattern signals in a colorectal cancer model by modulated electrohyperthermia

Cell Stress Chaperones. 2015 Jan;20(1):37-46. doi: 10.1007/s12192-014-0523-6. Epub 2014 Jun 29.


In modulated electrohyperthermia (mEHT) the enrichment of electric field and the concomitant heat can selectively induce cell death in malignant tumors as a result of elevated glycolysis, lactate production (Warburg effect), and reduced electric impedance in cancer compared to normal tissues. Earlier, we showed in HT29 colorectal cancer xenografts that the mEHT-provoked programmed cell death was dominantly caspase independent and driven by apoptosis inducing factor activation. Using this model here, we studied the mEHT-related cell stress 0-, 1-, 4-, 8-, 14-, 24-, 48-, 72-, 120-, 168- and 216-h post-treatment by focusing on damage-associated molecular pattern (DAMP) signals. Significant cell death response upon mEHT treatment was accompanied by the early upregulation (4-h post-treatment) of heat shock protein (Hsp70 and Hsp90) mRNA levels. In situ, the treatment resulted in spatiotemporal occurrence of a DAMP protein signal sequence featured by the significant cytoplasmic to cell membrane translocation of calreticulin at 4 h, Hsp70 between 14 and 24 h and Hsp90 between 24- and 216-h post-treatment. The release of high-mobility group box1 protein (HMGB1) from tumor cell nuclei from 24-h post-treatment and its clearance from tumor cells by 48 h was also detected. Our results suggest that mEHT treatment can induce a DAMP-related signal sequence in colorectal cancer xenografts that may be relevant for promoting immunological cell death response, which need to be further tested in immune-competent animals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calreticulin / metabolism
  • Colorectal Neoplasms / physiopathology*
  • Fluorescent Antibody Technique
  • HMGB1 Protein / metabolism
  • HSP70 Heat-Shock Proteins / genetics*
  • HSP70 Heat-Shock Proteins / metabolism*
  • HSP90 Heat-Shock Proteins / genetics*
  • HSP90 Heat-Shock Proteins / metabolism*
  • HT29 Cells
  • Humans
  • Hyperthermia, Induced
  • Mice, Inbred BALB C
  • Mice, Nude
  • RNA, Messenger / metabolism
  • Transplantation, Heterologous
  • Up-Regulation*


  • Calreticulin
  • HMGB1 Protein
  • HSP70 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • RNA, Messenger