Phosphofructokinase 1 Platelet Isoform Promotes β-Catenin Transactivation for Tumor Development.

Jong-Ho Lee,Dongming Xing,Jin Woong Chung,Linyong Du,Jinjie Ling,Zhiqiang An,Fei Shao,Sean Lu,Sang Seok Koh,Zhimin Lu,Rui Liu,Jichun Shao,Sun-Hee Leem

doi:10.3389/fonc.2020.00211

Abstract

Metabolism plays a critical role in direct regulation of a variety of cellular activities via metabolic enzymes and metabolites. Here, we demonstrate that phosphofructokinase 1 platelet isoform (PFKP), which catalyzes a rate-limiting reaction in glycolysis, promotes EGFR activation-induced nuclear translocation and activation of β-catenin, thereby enhancing the expression of its downstream genes CCND1 and MYC in human glioblastoma cells. Importantly, we showed that EGFR-phosphorylated PFKP Y64 has a critical role in AKT activation and AKT-mediated β-catenin S552 phosphorylation and subsequent β-catenin transactivation and promotion of tumor cell glycolysis, migration, invasion, proliferation, and brain tumor growth. These findings highlight a novel mechanism underlying a glycolytic enzyme-mediated β-catenin transactivation and underscore the integrated and reciprocal regulation of metabolism and gene expression, which are two fundamental biological processes in tumor development.

Highlights

Increased transcriptional activity of β-catenin, which is essential for cell proliferation, migration, invasion, and survival [1, 2], has been detected in many types of human cancer [3,4,5,6]. β-catenin transactivation leads to enhanced T-cell factor (TCF)/lymphoid enhancer factor (LEF)-driven transcription of genes, such as CCND1 and MYC [7,8,9]. β-catenin can be activated by Wnt ligands and by receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR), whose mutation or overexpression of EGFR gene occurs in many types of human cancer, including more than 50% of glioblastoma
We demonstrate that phosphofructokinase 1 (PFK1) platelet (PFKP) plays an instrumental role in EGFR activation-induced β-catenin transactivation in a PFKP Y64 phosphorylation-dependent manner, thereby regulating migration, invasion, and proliferation of glioblastomaPFKP Induces β-Catenin Activation (GBM) cells and brain tumor growth
The TCF/LEF-1 luciferase reporter analysis showed that depletion of PFKP expression largely inhibited EGF-induced β-catenin transactivation in U87/EGFR, LN229, and A549 cells (Figure 1C and Supplementary Figure S1C)

Summary

Introduction

Increased transcriptional activity of β-catenin, which is essential for cell proliferation, migration, invasion, and survival [1, 2], has been detected in many types of human cancer [3,4,5,6]. β-catenin transactivation leads to enhanced T-cell factor (TCF)/lymphoid enhancer factor (LEF)-driven transcription of genes, such as CCND1 (encoding cyclin D1) and MYC (encoding c-Myc) [7,8,9]. β-catenin can be activated by Wnt ligands and by receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR), whose mutation or overexpression of EGFR gene occurs in many types of human cancer, including more than 50% of glioblastomaPFKP Induces β-Catenin Activation (GBM) [10, 11]. Β-catenin can be activated by Wnt ligands and by receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR), whose mutation or overexpression of EGFR gene occurs in many types of human cancer, including more than 50% of glioblastoma. Our previous report showed that PFKP is the prominent PFK1 isoform in GBM cells and is overexpressed in human GBM specimens [26]. The activated PI3K and AKT enhances PFK1 activation and GLUT1 expression, thereby promoting aerobic glycolysis in cancer cells and brain tumorigenesis [27]. The role of PFKP in the EGFR activation-induced β-catenin transactivation of GBM cells remains unknown

Methods

Results

Conclusion