The influence of PFK-II overexpression on neuroblastoma patients’ survival may be dependent on the particular isoenzyme expressed, PFKFB3 or PFKFB4

Abstract

Background/AimDuring cancer progression metabolic reprogramming is observed in parallel to the alternation in transcriptional profiles of malignant cells. Recent studies suggest that metabolic isoenzymes of phosphofructokinase II (PFK-II) – PFKFB3 and PFKFB4, often induced in hypoxic environment, significantly contribute to enhancement of glucose metabolism and in consequence cancer progression.Materials and methodsUsing the publicly available data deposited in the R2 data base we performed a Kaplan–Meyer analysis for cancer patients divided into groups with high and low expression levels of PFKFB3/4, determined based on the median.ResultsOur data showed that high PFKFB3/4 expression significantly correlates with shorter overall survival in several cancers. Moreover, we found that neuroblastoma patients with poor overall survival and evidence free survival are characterized by high PFKFB3 and at the same time low PFKFB4 expression, whereas patients with high PFKFB4 expressions are characterized by significantly better overall survival/evidence free survival rates.ConclusionOur analysis clearly indicates that expression of PFKFB3/4 isoenzymes may have a key prognostic value for several cancers. What’s more, it seems that in neuroblastoma the prognostic value of PFK-II may be dependent on the relation between PFKFB3 and PFKFB4 isoenzyme expression, indicating that further studies analyzing the role of both cancer specific PFK-II isoenzymes are highly desired.

Therapeutic targeting of PFKFB3 and PFKFB4 in multiple myeloma cells under hypoxic conditions

“…The role of enhanced glucose breakdown in carcinogenesis is well known because the attenuation of glycolysis inhibits the growth, and decreases the survival, of cancer cells. High PFKFB3/4 expression is signi cantly correlated with shorter overall survival in several cancers, such as cervical squamous cell carcinoma, colon cancer, glioma, melanoma, and neuroblastoma [28]. In a previous study, a high amount of PFKFB4 was found to indicate a poor prognosis in breast cancer because it is related to increased rates of metastasis [29].…”

Canonical and Non-Canonical Roles of PFKFB3 in Brain Tumors

“…In brain tumors, including high-grade gliomas, PFKFB3 expression has been linked to poor survival [ 127 , 128 , 129 , 130 ]. However, targeted PFKFB3 inhibition may provide a therapeutic option for CNS tumor patients.…”

“…As such, efficacious delivery of chemotherapy is difficult with chemoresistance developing in most malignant CNS tumor patients. High PFKFB3 LOH at 10p14-p15, as well as low UBI2K4 expression levels in glioblastoma, has been shown to portend a poor prognosis with an overall poor survival [ 127 , 128 , 129 , 130 ].…”

“…Exogenous overexpression of UBI2K4 has been observed to decrease cell viability and growth in glioblastoma U87 cell lines without inducing a glycolytic effect, as there were no changes in lactate production [ 127 ]. Interestingly, high PFKFB4 expression is correlated with improved survival in glioblastoma and neuroblastoma patients [ 128 , 130 ].…”

“…Those with low PFKFB3:PFKFB4 ratios had a 9 month overall survival compared to 14 months for those with ratios greater than 7.7:1. High PFKFB3:PFKFB4 expression is associated with a 2.56 hazard ratio for worse overall survival and diminished evidence-free survival [ 130 ]. However, neuroblastomas with both high PFKFB3 expression and high PFKFB4 co-expression showed a 1.69 hazard ratio, indicating that PFKFB4 may offset negative effects caused by PFKFB3 [ 130 ].…”