Electromagnetic fields at mobile phone frequency induce apoptosis and inactivation of the multi‐chaperone complex in human epidermoid cancer cells

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Abstract
The exposure to non‐thermal microwave electromagnetic field (MW‐EMF) at 1.95 MHz, a frequency used in mobile communication, affects the refolding kinetics of eukaryotic proteins (Mancinelli et al., 2004). On these basis we have evaluated the in vivo effect of MW‐EMF in human epidermoid cancer KB cells. We have found that MW‐EMF induces time‐dependent apoptosis (45% after 3 h) that is paralleled by an about 2.5‐fold decrease of the expression of ras and Raf‐1 and of the activity of ras and Erk‐1/2. Although also the expression of Akt was reduced its activity was unchanged likely as a consequence of the increased expression of its upstream activator PI3K. In the same experimental conditions an about 2.5‐fold increase of the ubiquitination of ras and Raf‐1 was also found and the addition for 12 h of proteasome inhibitor lactacystin at 10 μM caused an accumulation of the ubiquitinated isoforms of ras and Raf‐1 and counteracted the effects of MW‐EMF on ras and Raf‐1 expression suggesting an increased proteasome‐dependent degradation induced by MW‐EMF. The exposure of KB cells to MW‐EMF induced a differential activation of stress‐dependent pathway with an increase of JNK‐1 activity and HSP70 and 27 expression and with a reduction of p38 kinase activity and HSP90 expression. The overexpression of HSP90 induced by transfection of KB cells with a plasmid encoding for the factor completely antagonized the apoptosis and the inactivation of the ras → Erk‐dependent survival signal induced by MW‐EMF. Conversely, the inhibition of Erk activity induced by 12 h exposure to 10 mM Mek‐1 inhibitor U0126 antagonized the effects induced by HSP90 transfection on apoptosis caused by MW‐EMF. In conclusion, these results demonstrate for the first time that MW‐EMF induces apoptosis through the inactivation of the ras → Erk survival signaling due to enhanced degradation of ras and Raf‐1 determined by decreased expression of HSP90 and the consequent increase of proteasome dependent degradation.