Stress-induced, p53-mediated tumor growth inhibition of melanoma by modulated electrohyperthermia in mouse models without major immunogenic effects

Balázs Besztercei, Tamás Vancsik, Anett Benedek, Enikő Major, Mbuotidem J. Thomas, Csaba A. Schvarcz, T. Krenács, Z. Benyó, Andrea Balogh

Research output: Contribution to journalArticle

Abstract

Modulated electrohyperthermia (mEHT), an innovative complementary technique of radio-, chemo-, and targeted oncotherapy modalities, can induce tumor apoptosis and contribute to a secondary immune-mediated cancer death. Here, we tested the efficiency of high-fever range (~42C) mEHT on B16F10 melanoma both in cell culture and allograft models. In vivo, mEHT treatment resulted in significant tumor size reduction when repeated three times, and induced major stress response as indicated by upregulated cytoplasmic and cell membrane hsp70 levels. Despite the increased PUMA and apoptosis-inducing factor 1, and moderate rise in activated-caspase-3, apoptosis was not significant. However, phospho-H2AX indicated DNA double-strand breaks, which upregulated p53 protein and its downstream cyclin-dependent kinase inhibitors p21waf1 and p27kip. Combined in vitro treatment with mEHT and the p53 activator nutlin-3a additively reduced cell viability compared to monotherapies. Though mEHT promoted the release of damage-associated molecular pattern (DAMP) damage signaling molecules hsp70, HMGB1 and ATP to potentiate the tumor immunogenicity of melanoma allografts, it reduced MHC-I and melan-A levels in tumor cells. This might explain why the number of cytotoxic T cells was moderately reduced, while the amount of natural killer (NK) cells was mainly unchanged and only macrophages increased significantly. Our results suggest that mEHT-treatment-related tumor growth control was primarily mediated by cell-stress-induced p53, which upregulated cyclin-dependent kinase inhibitors. The downregulated tumor antigen-presenting machinery may explain the reduced cytotoxic T-cell response despite increased DAMP signaling. Decreased tumor antigen and MHC-I levels suggest that natural killer (NK) cells and macrophages were the major contributors to tumor eradication.

Original languageEnglish
Article number4019
JournalInternational journal of molecular sciences
Volume20
Issue number16
DOIs
Publication statusPublished - Aug 2 2019

Fingerprint

mice
Tumors
Melanoma
tumors
Growth
Neoplasms
apoptosis
Cell death
T-cells
Cyclin-Dependent Kinases
Macrophages
Neoplasm Antigens
macrophages
Allografts
Natural Killer Cells
antigens
Antigens
damage
Cells
MART-1 Antigen

Keywords

  • Electrohyperthermia
  • Hsp70
  • Melanoma
  • MHC-I
  • Stress response
  • Tumor growth arrest

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Stress-induced, p53-mediated tumor growth inhibition of melanoma by modulated electrohyperthermia in mouse models without major immunogenic effects. / Besztercei, Balázs; Vancsik, Tamás; Benedek, Anett; Major, Enikő; Thomas, Mbuotidem J.; Schvarcz, Csaba A.; Krenács, T.; Benyó, Z.; Balogh, Andrea.

In: International journal of molecular sciences, Vol. 20, No. 16, 4019, 02.08.2019.

Research output: Contribution to journalArticle

Besztercei, Balázs ; Vancsik, Tamás ; Benedek, Anett ; Major, Enikő ; Thomas, Mbuotidem J. ; Schvarcz, Csaba A. ; Krenács, T. ; Benyó, Z. ; Balogh, Andrea. / Stress-induced, p53-mediated tumor growth inhibition of melanoma by modulated electrohyperthermia in mouse models without major immunogenic effects. In: International journal of molecular sciences. 2019 ; Vol. 20, No. 16.
@article{dedbf1aad6324a29b0deeb2e583ddf8e,
title = "Stress-induced, p53-mediated tumor growth inhibition of melanoma by modulated electrohyperthermia in mouse models without major immunogenic effects",
abstract = "Modulated electrohyperthermia (mEHT), an innovative complementary technique of radio-, chemo-, and targeted oncotherapy modalities, can induce tumor apoptosis and contribute to a secondary immune-mediated cancer death. Here, we tested the efficiency of high-fever range (~42◦C) mEHT on B16F10 melanoma both in cell culture and allograft models. In vivo, mEHT treatment resulted in significant tumor size reduction when repeated three times, and induced major stress response as indicated by upregulated cytoplasmic and cell membrane hsp70 levels. Despite the increased PUMA and apoptosis-inducing factor 1, and moderate rise in activated-caspase-3, apoptosis was not significant. However, phospho-H2AX indicated DNA double-strand breaks, which upregulated p53 protein and its downstream cyclin-dependent kinase inhibitors p21waf1 and p27kip. Combined in vitro treatment with mEHT and the p53 activator nutlin-3a additively reduced cell viability compared to monotherapies. Though mEHT promoted the release of damage-associated molecular pattern (DAMP) damage signaling molecules hsp70, HMGB1 and ATP to potentiate the tumor immunogenicity of melanoma allografts, it reduced MHC-I and melan-A levels in tumor cells. This might explain why the number of cytotoxic T cells was moderately reduced, while the amount of natural killer (NK) cells was mainly unchanged and only macrophages increased significantly. Our results suggest that mEHT-treatment-related tumor growth control was primarily mediated by cell-stress-induced p53, which upregulated cyclin-dependent kinase inhibitors. The downregulated tumor antigen-presenting machinery may explain the reduced cytotoxic T-cell response despite increased DAMP signaling. Decreased tumor antigen and MHC-I levels suggest that natural killer (NK) cells and macrophages were the major contributors to tumor eradication.",
keywords = "Electrohyperthermia, Hsp70, Melanoma, MHC-I, Stress response, Tumor growth arrest",
author = "Bal{\'a}zs Besztercei and Tam{\'a}s Vancsik and Anett Benedek and Enikő Major and Thomas, {Mbuotidem J.} and Schvarcz, {Csaba A.} and T. Kren{\'a}cs and Z. Beny{\'o} and Andrea Balogh",
year = "2019",
month = "8",
day = "2",
doi = "10.3390/ijms20164019",
language = "English",
volume = "20",
journal = "International Journal of Molecular Sciences",
issn = "1661-6596",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "16",

}

TY - JOUR

T1 - Stress-induced, p53-mediated tumor growth inhibition of melanoma by modulated electrohyperthermia in mouse models without major immunogenic effects

AU - Besztercei, Balázs

AU - Vancsik, Tamás

AU - Benedek, Anett

AU - Major, Enikő

AU - Thomas, Mbuotidem J.

AU - Schvarcz, Csaba A.

AU - Krenács, T.

AU - Benyó, Z.

AU - Balogh, Andrea

PY - 2019/8/2

Y1 - 2019/8/2

N2 - Modulated electrohyperthermia (mEHT), an innovative complementary technique of radio-, chemo-, and targeted oncotherapy modalities, can induce tumor apoptosis and contribute to a secondary immune-mediated cancer death. Here, we tested the efficiency of high-fever range (~42◦C) mEHT on B16F10 melanoma both in cell culture and allograft models. In vivo, mEHT treatment resulted in significant tumor size reduction when repeated three times, and induced major stress response as indicated by upregulated cytoplasmic and cell membrane hsp70 levels. Despite the increased PUMA and apoptosis-inducing factor 1, and moderate rise in activated-caspase-3, apoptosis was not significant. However, phospho-H2AX indicated DNA double-strand breaks, which upregulated p53 protein and its downstream cyclin-dependent kinase inhibitors p21waf1 and p27kip. Combined in vitro treatment with mEHT and the p53 activator nutlin-3a additively reduced cell viability compared to monotherapies. Though mEHT promoted the release of damage-associated molecular pattern (DAMP) damage signaling molecules hsp70, HMGB1 and ATP to potentiate the tumor immunogenicity of melanoma allografts, it reduced MHC-I and melan-A levels in tumor cells. This might explain why the number of cytotoxic T cells was moderately reduced, while the amount of natural killer (NK) cells was mainly unchanged and only macrophages increased significantly. Our results suggest that mEHT-treatment-related tumor growth control was primarily mediated by cell-stress-induced p53, which upregulated cyclin-dependent kinase inhibitors. The downregulated tumor antigen-presenting machinery may explain the reduced cytotoxic T-cell response despite increased DAMP signaling. Decreased tumor antigen and MHC-I levels suggest that natural killer (NK) cells and macrophages were the major contributors to tumor eradication.

AB - Modulated electrohyperthermia (mEHT), an innovative complementary technique of radio-, chemo-, and targeted oncotherapy modalities, can induce tumor apoptosis and contribute to a secondary immune-mediated cancer death. Here, we tested the efficiency of high-fever range (~42◦C) mEHT on B16F10 melanoma both in cell culture and allograft models. In vivo, mEHT treatment resulted in significant tumor size reduction when repeated three times, and induced major stress response as indicated by upregulated cytoplasmic and cell membrane hsp70 levels. Despite the increased PUMA and apoptosis-inducing factor 1, and moderate rise in activated-caspase-3, apoptosis was not significant. However, phospho-H2AX indicated DNA double-strand breaks, which upregulated p53 protein and its downstream cyclin-dependent kinase inhibitors p21waf1 and p27kip. Combined in vitro treatment with mEHT and the p53 activator nutlin-3a additively reduced cell viability compared to monotherapies. Though mEHT promoted the release of damage-associated molecular pattern (DAMP) damage signaling molecules hsp70, HMGB1 and ATP to potentiate the tumor immunogenicity of melanoma allografts, it reduced MHC-I and melan-A levels in tumor cells. This might explain why the number of cytotoxic T cells was moderately reduced, while the amount of natural killer (NK) cells was mainly unchanged and only macrophages increased significantly. Our results suggest that mEHT-treatment-related tumor growth control was primarily mediated by cell-stress-induced p53, which upregulated cyclin-dependent kinase inhibitors. The downregulated tumor antigen-presenting machinery may explain the reduced cytotoxic T-cell response despite increased DAMP signaling. Decreased tumor antigen and MHC-I levels suggest that natural killer (NK) cells and macrophages were the major contributors to tumor eradication.

KW - Electrohyperthermia

KW - Hsp70

KW - Melanoma

KW - MHC-I

KW - Stress response

KW - Tumor growth arrest

UR - http://www.scopus.com/inward/record.url?scp=85071369916&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071369916&partnerID=8YFLogxK

U2 - 10.3390/ijms20164019

DO - 10.3390/ijms20164019

M3 - Article

VL - 20

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 16

M1 - 4019

ER -