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.

No abstract

No abstract

No abstract

Human N-acetylgalactosamine-α2,6-sialyltransferase (hST6GalNAc I) is the major enzyme involved in the biosynthesis of sialyl-Tn antigen (sTn), which is known to be expressed in more than 80% of human carcinomas and correlated with poor prognosis in cancer patients. Athough high expression of hST6GalNAc I is associated with augmented proliferation, migration and invasion in various cancer cells, transcriptional mechanism regulating hST6GalNAc I gene expression remains largely unknown. In this study, we found that hST6GalNAc I gene expression was markedly augmented by curcumin in HCT116 human colon carcinoma cells. To understand the molecular mechanism for the upregulation of hST6GalNAc I gene expression by curcumin in HCT116 cells, we first determined the transcriptional start site of hST6GalNAc I gene by 5′-RACE and cloned the proximal hST6GalNAc I 5′-flanking region spanning about 2 kb by PCR. Functional analysis of the hST6GalNAc I 5′ flanking region of hST6GalNAc I by sequential 5′-deletion, transient transfection of reporter gene constructs and luciferase reporter assays showed that -378/-136 region is essential for maximal activation of transcription in response to curcumin in HCT 116 cells. This region includes putative binding sites for transcription factors c-Ets-1, NF-1, GATA-1, ER-α, YY1, and GR-α. ChIP analysis and site-directed mutagenesis demonstrated that estrogen receptor α (ER-α) binding site (nucleotides -248/-238) in this region is crucial for hST6GalNAc I gene transcription in response to curcumin stimulation in HCT116 cells. The transcription activity of hST6GalNAc I gene induced by curcumin in HCT116 cells was strongly inhibited by PKC inhibitor (Gö6983) and ERK inhibitor (U0126). These results suggest that curcumin-induced hST6GalNAc I gene expression in HCT116 cells is modulated through PKC/ERKs signal pathway.