N6-Isopentenyladenosine Impairs Mitochondrial Metabolism through Inhibition of EGFR Translocation on Mitochondria in Glioblastoma Cells

SIMPLE SUMMARY: Glioblastomas are aggressive and incurable brain tumors, being resistant to therapy. N6-isopentenyladenosine (i6A or iPA) is a naturally derived molecule that has been studied for its anti-glioma effects. We found that iPA treatment induces an alteration of cellular metabolism due to inhibition of EGFR translocation on mitochondria and activation of cell death following PUMA upregulation. Our findings suggest that inducing dysfunctional mitochondria through iPA might be a promising therapeutic avenue in the treatment of glioblastoma. ABSTRACT: Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor and is poorly susceptible to cytotoxic therapies. Amplification of the epidermal growth factor receptor (EGFR) and deletion of exons 2 to 7, which generates EGFR variant III (vIII), are the most common molecular alterations of GBMs that contribute to the aggressiveness of the disease. Recently, it has been shown that EGFR/EGFRvIII-targeted inhibitors enhance mitochondrial translocation by causing mitochondrial accumulation of these receptors, promoting the tumor drug resistance; moreover, they negatively modulate intrinsic mitochondria-mediated apoptosis by sequestering PUMA, leading to impaired apoptotic response in GBM cells. N6-isopentenyladenosine (i6A or iPA), a cytokinin consisting of an adenosine linked to an isopentenyl group deriving from the mevalonate pathway, has antiproliferative effects on numerous tumor cells, including GBM cells, by inducing cell death in vitro and in vivo. Here, we observed that iPA inhibits the mitochondrial respiration in GBM cells by preventing the translocation of EGFR/EGFRvIII to the mitochondria and allowing PUMA to interact with them by promoting changes in mitochondrial activity, thus playing a critical role in cell death. Our findings clearly demonstrate that iPA interferes with mitochondrial bioenergetic capacity, providing a rationale for an effective strategy for treating GBM.