Electro-hyperthermia inhibits glioma tumorigenicity through the induction of E2F1-mediated apoptosis

Abstract

Purpose

Modulated electro-hyperthermia (mEHT), also known as oncothermia, shows remarkable treatment efficacies to various types of tumors, including glioma. The aim of the present study was to investigate the molecular mechanism underlying phenotypic changes in oncothermic cancer cells.

Materials and methods

U87-MG and A172 human glioma cells were exposed to mEHT (42℃/60 min) three times with a 2-day interval and subsequently tested for growth inhibition using MTS, FACS and microscopic analysis. To obtain insights into the molecular changes in response to mEHT, global changes in gene expression were examined using RNA sequencing. For in vivo evaluation of mEHT, we used U87-MG glioma xenografts grown in nude mice.

Results

mEHT inhibited glioma cell growth through the strong induction of apoptosis. The transcriptomic analysis of differential gene expression under mEHT showed that the anti-proliferative effects were induced through a subset of molecular alterations, including the upregulation of E2F1 and CPSF2 and the downregulation of ADAR and PSAT1. Subsequent Western blotting revealed that mEHT increased the levels of E2F1 and p53 and decreased the level of PARP-1, accelerating apoptotic signaling in glioma cells. mEHT significantly suppressed the growth of human glioma xenografts in nude mice. We also observed that mEHT dramatically reduced the portion of CD133+ glioma stem cell population and suppressed cancer cell migration and sphere formation.

Conclusions

These findings suggest that mEHT suppresses glioma cell proliferation and mobility through the induction of E2F1-mediated apoptosis and might be an effective treatment for eradicating the brain tumors.