Analysis of Malignant Melanoma Cell Lines Exposed to Hypoxia Reveals the Importance of PFKFB4 Overexpression for Disease Progression

Anticancer Res. 2018 Dec;38(12):6745-6752. doi: 10.21873/anticanres.13044.

Abstract

Background/aim: Most melanomas develop in hypoxic conditions. Since hypoxia via HIF-1 induces glycolysis, a process essential for malignant melanoma growth/survival, the goal of this study was to analyze the influence of hypoxia on the expression of HIF-1 target genes involved in glucose metabolism.

Materials and methods: The response of melanoma cell lines to hypoxic conditions was analyzed by RT-PCR and western blotting. A Kaplan-Meier survival analysis for patients with high and low expression level of PFKFB4 was performed. Further analysis of patients' data was performed using the R/Bioconductor environment.

Results: Induction of PFKFB4 gene expression can be considered a crucial mechanism behind glycolysis enhancement in hypoxic melanoma cells. Analysis of a publicly available database revealed that high PFKFB4 expression contributes to poor prognosis of melanoma patients.

Conclusion: Currently available anti-melanoma therapeutic strategies may significantly benefit from agents targeting PFKFB4 activity.

Keywords: HIF-1; Hypoxia; PFKFB4; malignant melanoma.

MeSH terms

  • Cell Hypoxia / physiology
  • Cell Line, Tumor
  • Disease Progression
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Melanoma / mortality
  • Melanoma / pathology*
  • Melanoma, Cutaneous Malignant
  • Microarray Analysis
  • Neoplasm Metastasis
  • Oxygen / pharmacology*
  • Phosphofructokinase-2 / genetics*
  • Phosphofructokinase-2 / physiology
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / mortality
  • Skin Neoplasms / pathology*
  • Survival Analysis
  • Up-Regulation / drug effects
  • Up-Regulation / genetics

Substances

  • PFKFB4 protein, human
  • Phosphofructokinase-2
  • Oxygen