Stabilization of phosphofructokinase 1 platelet isoform by AKT promotes tumorigenesis

Abstract

Phosphofructokinase 1 (PFK1) plays a critical role in glycolysis; however, its role and regulation in tumorigenesis are not well understood. Here, we demonstrate that PFK1 platelet isoform (PFKP) is the predominant PFK1 isoform in human glioblastoma cells and its expression correlates with total PFK activity. We show that PFKP is overexpressed in human glioblastoma specimens due to an increased stability, which is induced by AKT activation resulting from phosphatase and tensin homologue (PTEN) loss and EGFR-dependent PI3K activation. AKT binds to and phosphorylates PFKP at S386, and this phosphorylation inhibits the binding of TRIM21 E3 ligase to PFKP and the subsequent TRIM21-mediated polyubiquitylation and degradation of PFKP. PFKP S386 phosphorylation increases PFKP expression and promotes aerobic glycolysis, cell proliferation, and brain tumor growth. In addition, S386 phosphorylation in human glioblastoma specimens positively correlates with PFKP expression, AKT S473 phosphorylation, and poor prognosis. These findings underscore the potential role and regulation of PFKP in human glioblastoma development.

TRIM21 and PHLDA3 negatively regulate the crosstalk between the PI3K/AKT pathway and PPP metabolism

“…3d). Re-expression of WT TRIM21, but not the E3 ligase-dead mutant (C16A, C31A and H33W) 29 , in TRIM21 knockout cells could significantly reduce the levels of G6PD as well as the PPP metabolites ( Fig. 3d), strongly supporting the notion that TRIM21 is the E3 ligase that controls G6PD degradation.…”

TRIM21 and PHLDA3 Negatively Regulate the Cross-Talk between the PI3K/AKT Pathway and PPP Metabolism

“…As predicted for an E3 ligase, TRIM21 knockout could increase both the protein and enzymatic activity of G6PD, as well as the levels of PPP metabolites (Figure 3D). Overexpression of WT TRIM21, but not E3 ligase dead mutant (C16A, C31A and H33W) 28 , in TRIM21 -knockout cells could significantly reduce the levels of G6PD as well as PPP metabolites (Figure 3D), strongly supporting the notion that TRIM21 is the E3 ligase that controls G6PD degradation. Increased PPP activity in TRIM21 -knockout cells also led increased cell growth and tumor volume in vitro and in vivo , respectively, demonstrating the significant role of TRIM21 in negatively regulating PPP and cell growth (Figure 3E; S3A and S3B).…”

“…Our analysis demonstrates TRIM21 expression levels are negatively correlated with PI3K activity in various human cancers, implying that TRIM21 may act as a potential tumor suppressor. TRIM21 can also promote phosphofructokinase 1 (PFK1) degradation 28 . Therefore, TRIM21 may act at multiple nodes to control normal cell metabolism and cancer metabolic reprogramming.…”

Identification of a Subtype of Hepatocellular Carcinoma with Poor Prognosis Based on Expression of Genes within the Glucose Metabolic Pathway

“…Our results showed that the platelet isoform of PFK1 gene (PFKP) was significantly increased in HCC, which is also an independent predictor for OS, but the other two isoforms PFKM and PFKL were not. PFKP has been reported to contribute to metabolic reprogramming and maintain cell proliferation in clear cell renal carcinoma [35], and promote tumorigenesis in glioblastoma [36], but has not been well studied in HCC. It could be a potential therapeutic target in HCC and worth further functional study.…”