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

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.

N6‐isopentenyladenosine inhibits aerobic glycolysis in glioblastoma cells by targeting PKM2 expression and activity

“…iPA treatment at 10 μ m for 48 h caused necroptosis in GBM cells lines and GBM4 primary cell isolated by cancer biopsy through the activation of necroptosis markers, whereas, in treated NHA cells, apoptotic events were irrelevant. Moreover, in a recent study, we demonstrated that iPA interferes with mitochondrial bioenergetic capacity in the same cells as those used in the present study [24]. Given that aerobic glycolysis has a key role for most tumor cells in the maintainance of rapid growth and in metastasis, we tested whether IPA inhibited tumor cell growth via blocking the aerobic glycolysis in GBM cells.…”

“…In another study, we demonstrated that iPA treatment induced necroptosis in GBM cells through the activation of receptor‐interacting protein kinase 1 (RIPK1), receptor‐interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain‐like protein, allowing the necrosome formation and the execution of necroptotic process [ 23 ]. Lastly, we have reported that IPA treatment inhibited mitochondrial respiration in U87MG cells and the same cells engineered to over‐express EGFR wild‐type (U87MG‐EGFRwt) or EGFRvIII (U87MG‐EGFR‐vIII), as well as in primary GBM patients‐derived cells, by preventing the translocation of EGFR/EGFRvIII on the mitochondria through the inhibition of Y845 phosphorylation of EGFR [ 24 ]. In the present study, we observed that this natural compound inhibited aerobic glycolysis in the GBM cells described above by targeting PKM2 expression.…”

NDUFA12 as a Functional Target of the Anticancer Compound Ertredin in Human Hepatoma Cells As Revealed by Label-Free Chemical Proteomics

“…Several studies have shown that apoptosis inducers and EGFR/EGFRvIII-targeted inhibitors enhance mitochondrial translocation of EGFR/EGFRvIII and induce mitochondrial accumulation of these receptors, thereby promoting drug resistance in tumors. Since cancer cells expressing abundant EGFRvIII are resistant to growth inhibition and apoptosis, this provides a mechanism for cancer cell survival. − In this study, we suggest that Ertredin treatment may improve the limitation of drug resistance in cancer cells with high mitochondrial EGFRvIII expression.…”

Blockage of EGFR/AKT and mevalonate pathways synergize the antitumor effect of temozolomide by reprogramming energy metabolism in glioblastoma

“…EGFR translocation on mitochondria is reported to regulate mitochondria dynamics by interacting with MFN1 and disturbing MFN1 polymerization [ 54 ]. In gliomas, inhibition of EGFR translocation on mitochondria by iPA promotes PUMA‐induced cell death [ 55 ]. These findings implied the correlation between mitochondria‐localized EGFR and the balance of mitochondrial fission/fusion, high level of EGFR increased the number of mitochondria in tumor cells.…”