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

Andocs, Gabor and Meggyeshazi, Nora and Balogh, Lajos and Spisak, Sandor and Maros, Mate Elod and Balla, Peter and Kiszner, Gergo and Teleki, Ivett and Kovago, Csaba and Krenacs, Tibor (2015) Upregulation of heat shock proteins and the promotion of damage-associated molecular pattern signals in a colorectal cancer model by modulated electrohyperthermia. Cell Stress and Chaperones, 20 (1). pp. 37-46. ISSN 1355-8145

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Abstract

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 d eath was dominantly cas- pase independent and driven by apoptosis inducing fac- tor 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 spatio- temporal occurrence of a DAMP protein signal sequence featured by the significant c ytoplasmic 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 pro- tein (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 treat- ment can induce a DAMP-rela ted 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.

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