Revisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells

Abstract

Aerobic glycolysis is an emerging hallmark of many human cancers, as cancer cells are defined as a “metabolically abnormal system”. Carbohydrates are metabolically reprogrammed by its metabolizing and catabolizing enzymes in such abnormal cancer cells. Normal cells acquire their energy from oxidative phosphorylation, while cancer cells acquire their energy from oxidative glycolysis, known as the “Warburg effect”. Energy–metabolic differences are easily found in the growth, invasion, immune escape and anti-tumor drug resistance of cancer cells. The glycolysis pathway is carried out in multiple enzymatic steps and yields two pyruvate molecules from one glucose (Glc) molecule by orchestral reaction of enzymes. Uncontrolled glycolysis or abnormally activated glycolysis is easily observed in the metabolism of cancer cells with enhanced levels of glycolytic proteins and enzymatic activities. In the “Warburg effect”, tumor cells utilize energy supplied from lactic acid-based fermentative glycolysis operated by glycolysis-specific enzymes of hexokinase (HK), keto-HK-A, Glc-6-phosphate isomerase, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase, phosphofructokinase (PFK), phosphor-Glc isomerase (PGI), fructose-bisphosphate aldolase, phosphoglycerate (PG) kinase (PGK)1, triose phosphate isomerase, PG mutase (PGAM), glyceraldehyde-3-phosphate dehydrogenase, enolase, pyruvate kinase isozyme type M2 (PKM2), pyruvate dehydrogenase (PDH), PDH kinase and lactate dehydrogenase. They are related to glycolytic flux. The key enzymes involved in glycolysis are directly linked to oncogenesis and drug resistance. Among the metabolic enzymes, PKM2, PGK1, HK, keto-HK-A and nucleoside diphosphate kinase also have protein kinase activities. Because glycolysis-generated energy is not enough, the cancer cell-favored glycolysis to produce low ATP level seems to be non-efficient for cancer growth and self-protection. Thus, the Warburg effect is still an attractive phenomenon to understand the metabolic glycolysis favored in cancer. If the basic properties of the Warburg effect, including genetic mutations and signaling shifts are considered, anti-cancer therapeutic targets can be raised. Specific therapeutics targeting metabolic enzymes in aerobic glycolysis and hypoxic microenvironments have been developed to kill tumor cells. The present review deals with the tumor-specific Warburg effect with the revisited viewpoint of recent progress.

Regulative Roles of Metabolic Plasticity Caused by Mitochondrial Oxidative Phosphorylation and Glycolysis on the Initiation and Progression of Tumorigenesis

“…Once glucose enters the cell, glycolysis is catalyzed by HK, and PK catalyzes the “export”. PFK is the most important rate-limiting enzyme of glycolysis, which can quickly react with ATP/ADP, citric acid, and other alternative fuels, such as fatty acids, ketones, and hormones, to regulate the whole process of glycolysis [ 141 ].…”

Phosphofructokinase Platelet Overexpression Accelerated Colorectal Cancer Cell Growth and Motility

“…Previous studies have reported that PFKP is overexpressed in several human cancers 25 , 26 , 27 . To confirm these findings, we downloaded the expression levels of PFKP from the GTEx database (for human normal tissues) and TCGA database (for human tumor tissues).…”

“…Three isoforms of PFK-1 have been noted, with different proportions in different cancers [22]. Among these isoforms, PFKP is frequently abnormally expressed in lung cancer, breast cancer, kidney cancer, and oral squamous cell carcinoma and has a poor effect on cancer behavior [23][24][25][26]. However, the clinical effect and biological role of PFKP in colorectal cancer remain unclear.…”

Warburg effect‐related risk scoring model to assess clinical significance and immunity characteristics of glioblastoma

“…Targeting the Warburg effect is currently considered a promising cancer therapy strategy, 53 and drugs that target the metabolic enzymes involved in aerobic glycolysis have been explored in GBM. 54,55 This is the first study to target Warburg effect-related genes for drug sensitivity and obtain the drug BEC, to which MPC1 is highly sensitive.…”