PGK1 contributes to tumorigenesis and sorafenib resistance of renal clear cell carcinoma via activating CXCR4/ERK signaling pathway and accelerating glycolysis

Abstract

Phosphoglycerate kinase 1 (PGK1) has complicated and multiple functions in cancer occurrence, tumor progression and drug resistance. Sorafenib is the first-line treatment targeted drug for patients with kidney renal clear cell carcinoma (KIRC) as a tyrosine kinase inhibitor, but sorafenib resistance is extremely common to retard therapy efficiency. So far, it is unclear whether and how PGK1 is involved in the pathogenesis and sorafenib resistance of KIRC. Herein, the molecular mechanisms of PGK1-mediated KIRC progression and sorafenib resistance have been explored by comprehensively integrative studies using biochemical approaches, mass spectrometry (MS) identification, microarray assay, nude mouse xenograft model and bioinformatics analysis. We have confirmed PGK1 is specifically upregulated in KIRC based on the transcriptome data generated by our own gene chip experiment, proteomics identification and the bioinformatics analysis for five online transcriptome datasets, and PGK1 upregulation in tumor tissues and serum is indicative with poor prognosis of KIRC patients. In the KIRC tissues, a high expression of PGK1 is often accompanied with an increase of glycolysis-related enzymes and CXCR4. PGK1 exhibits pro-tumorigenic properties in vitro and in a xenograft tumor model by accelerating glycolysis and inducing CXCR4-mediated phosphorylation of AKT and ERK. Moreover, PGK1 promotes sorafenib resistance via increasing CXCR4-mediated ERK phosphorylation. In conclusion, PGK1-invovled metabolic reprogramming and activation of CXCR4/ERK signaling pathway contributes to tumor growth and sorafenib resistance of KIRC.

Mining TCGA Database for Genes with Prognostic Value in Breast Cancer

“…In transformed cells, it is highly expressed in ovarian cancer [ 45 ]. Beside the above-mentioned activities, PGK1 is responsible for drug resistance in malignancy, however the exact mechanism is not known [ 37 ]. A possible mechanism to overcome drug resistance induced by sorafenib in cancer cells with high PGK1 expression might be the inhibition of the kinase with small inhibitors ( Figure 9 ).…”

Special issue “The advance of solid tumor research in China”: Multi‐omics analysis based on 1311 clear cell renal cell carcinoma samples identifies a glycolysis signature associated with prognosis and treatment response

“…24 Numerous enzymes and biomarkers involved in the glycolytic process would be dysregulated in ccRCC. 25,26 Thus, representative signatures or effective classification of glycolytic genes would be valuable for the diagnosis and prognosis of ccRCC.…”

“…The Warburg effect has been a vital hallmark of various kinds of tumors, importantly, aerobic glycolysis supports adequate ATP for cancer cell 24 . Numerous enzymes and biomarkers involved in the glycolytic process would be dysregulated in ccRCC 25,26 . Thus, representative signatures or effective classification of glycolytic genes would be valuable for the diagnosis and prognosis of ccRCC.…”

IMP4 Silencing Inhibits the Malignancy of Lung Adenocarcinoma via ERK Pathway

“…ERK signalling has recently emerged as a critical modulator of glycolysis during tumorigenesis [ 9 ]. He et al [ 25 ] reported that PGK1 contributes to the growth of renal clear cell carcinoma by activating CXCR4/ERK signalling and promoting glycolysis. In this study, we demonstrated that IMP4 silencing inhibited the activation of ERK signalling in LUAD cells.…”