UCP2 as a Potential Biomarker for Adjunctive Metabolic Therapies in Tumor Management

Abstract

Glioblastoma (GBM) remains one of the most lethal primary brain tumors in both adult and pediatric patients. Targeting tumor metabolism has emerged as a promising-targeted therapeutic strategy for GBM and characteristically resistant GBM stem-like cells (GSCs). Neoplastic cells, especially those with high proliferative potential such as GSCs, have been shown to upregulate UCP2 as a cytoprotective mechanism in response to chronic increased reactive oxygen species (ROS) exposure. This upregulation plays a central role in the induction of the highly glycolytic phenotype associated with many tumors. In addition to shifting metabolism away from oxidative phosphorylation, UCP2 has also been implicated in increased mitochondrial Ca2+ sequestration, apoptotic evasion, dampened immune response, and chemotherapeutic resistance. A query of the CGGA RNA-seq and the TCGA GBMLGG database demonstrated that UCP2 expression increases with increased WHO tumor-grade and is associated with much poorer prognosis across a cohort of brain tumors. UCP2 expression could potentially serve as a biomarker to stratify patients for adjunctive anti-tumor metabolic therapies, such as glycolytic inhibition alongside current standard of care, particularly in adult and pediatric gliomas. Additionally, because UCP2 correlates with tumor grade, monitoring serum protein levels in the future may allow clinicians a relatively minimally invasive marker to correlate with disease progression. Further investigation of UCP2’s role in metabolic reprogramming is warranted to fully appreciate its clinical translatability and utility.

The Chemistry of Reactive Oxygen Species (ROS) Revisited: Outlining Their Role in Biological Macromolecules (DNA, Lipids and Proteins) and Induced Pathologies

“…UCP2 expression is associated with cancer and modulates energy metabolism in response to elevated ROS levels [ 71 ]. Overexpression of UCP2 is found in leukaemia, ovarian, bladder, oesophageal, testicular, colorectal, kidney, pancreatic, lung and prostate tumours [ 72 ]. The effect of UCP2 on ATP concentrations varies according to cell type.…”

Genipin, an Inhibitor of UCP2 as a Promising New Anticancer Agent: A Review of the Literature

“…When UCP2 is upregulated, the opposite occurs, in that the exit of anions and protons from the matrix is facilitated. Although the mechanism by which UCP2 facilitates this proton transport is not fully understood, by allowing protons to leak across the IMM, the driving force behind ATP production through the electron transport chain is decreased, resulting in heat-energy release [ 2 , 11 , 13 ]. In addition to mitochondrial uncoupling, recent studies revealed that UCP2 plays an important role in the mitochondrial transport of C4 metabolites for NADPH production required for cancer cell growth ( Figure 1 ) [ 14 , 15 , 16 ].…”

“…Additionally, this shift in metabolism has been shown to increase cell proliferation as long as the supply of glucose is unlimited. A recent study suggests that cells shut off mitochondrial cellular respiration by increasing the expression of mitochondrial uncoupling protein 2 (UCP2) in an effort to mitigate the effect of cytotoxic reactive oxygen species (ROS), thereby inducing the Warburg effect through UCP2 upregulation [ 2 ].…”

The Acidic Brain—Glycolytic Switch in the Microenvironment of Malignant Glioma

“…Crosstalk between the immune checkpoint and metabolic pathways may profoundly impact tumor cell evasion from immune system recognition. For instance, in glioma, uncoupling protein (UCP)2 has been proposed to link the glycolytic switch to dampened immune response [ 156 ].…”