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.

Keywords: Glioblastoma; Warburg effect; biomarker; cancer; glioma; metabolism; precision-medicine; uncoupling protein 2 (UCP2).

Figure 1

High UCP2 expression is indicative of advanced tumor-grade and is associated with decreased survival. (A) UCP2 upregulation has many downstream consequences including worse prognosis. (B) TCGA_GBM database platform HG-U133A containing 10 non-tumor and 528 GBM tumor samples shows UCP2 is upregulated in tumor vs. non-tumor (p= 1.3E-05). (C) UCP2 expression correlates with tumor grade as seen in query of CGGA database including 625 low-grade and 388 high-grade gliomas (Grade II vs. Grade III p= 4.2E-02, Grade II vs. Grade IV. p= 2.4E-13, Grade III vs. Grade IV p= 6.3E-07). (D) Elevated UCP2 expression is indicative of worse prognosis in survival data from the TCGA GBMLGG dataset containing 515 low-grade and 152 high-grade tumors. (E) Elevated UCP2 expression is indicative of worse prognosis in survival data from the CGGA dataset. (Expression data were analyzed via pairwise group comparison using p-value with Bonferroni correction. Kaplan–Meyer data were analyzed via computation of Log-rank p-values).

Figure 2

Therapeutic implications of tumor UCP2 expression. UCP2 can be directly measured in tumor tissue and compared to baseline UCP2 expression levels. Tumors with high expression likely to exhibit carbohydrate dysregulation may benefit from adjunctive metabolic treatments such as glycolytic inhibition. Basal levels of UCP2 can be used to monitor tumor progression with potential serum measurements at follow-up. In tumors where UCP2 is inhibited or tumoral expression of UCP2 is very low, mitochondrial metabolism may remain intact suggesting an oxidative phosphorylation inhibitor may be warranted.