Glycolysis gene expression analysis and selective metabolic advantage in the clinical progression of colorectal cancer

Abstract

Production of lactate even in the presence of sufficient levels of oxygen (aerobic glycolysis) seems the prevalent energy metabolism pathway in cancer cells. The analysis of altered expression of effectors causing redirection of glucose metabolism would help to characterize this phenomenon with possible therapeutic implications. We analyzed mRNA expression of the key enzymes involved in aerobic glycolysis in normal mucosa (NM), primary tumor (PT) and liver metastasis (LM) of colorectal cancer (CRC) patients (pts) who underwent primary tumor surgery and liver metastasectomy. Tissues of 48 CRC pts were analyzed by RT-qPCR for mRNA expression of the following genes: hexokinase-1 (HK-1) and 2 (HK-2), embryonic pyruvate kinase (PKM-2), lactate dehydrogenase-A (LDH-A), glucose transporter-1 (GLUT-1), voltage-dependent anion-selective channel protein-1 (VDAC-1). Differences in the expression of the candidate genes between tissues and associations with clinical/pathologic features were studied. GLUT-1, LDH-A, HK-1, PKM-2 and VDAC-1 mRNA expression levels were significantly higher in PT/LM tissues compared with NM. There was a trend for higher expression of these genes in LM compared with PT tissues, but differences were statistically significant for LDH-A expression only. RAS mutation-positive disease was associated with high GLUT-1 mRNA expression levels only. Right-sided colon tumors showed significantly higher GLUT-1, PKM-2 and LDH-A mRNA expression levels. High glycolytic profile was significantly associated with poor prognosis in 20 metastatic, RAS-mutated pts treated with first-line chemotherapy plus Bevacizumab. Altered expression of effectors associated with upregulated glucose uptake and aerobic glycolysis occurs in CRC tissues. Additional analyses are warranted for addressing the role of these changes in anti-angiogenic resistance and for developing novel therapeutics.

Phosphoenolpyruvate from Glycolysis and PEPCK Regulate Cancer Cell Fate by Altering Cytosolic Ca2+

“…Several c-Myc targets modulated by PEP/Ca 2+ (i.e., Glut1, LDH-A) are associated with clinical colorectal cancer progression [35] and are also induced by K-Ras, commonly mutated in these cancers. Regulation of other targets such as glutaminase (GLS1) and the cytosolic isoform of serine hydroxymethyltransferase (cSHMT) suggest changes in the metabolic layout in agreement with the Warburg effect phenotype [23,36].…”

Characteristics of Differently Located Colorectal Cancers Support Proximal and Distal Classification: A Population-Based Study of 57,847 Patients

“…In other studies, risk factors including black race and a history of cancer or diabetes were closely related to RCC, while factors including white race, smoking, and high alcohol intake were closely associated with both LCC and ReC[15–19]. Recent studies indicated that LCC had higher concentrations of human DNA in the stools than RCC[20], while RCC showed significantly higher mRNA expression levels of glycolysis genes than LCC[21]. Differences were also observed between proximal and distal colon cancers in common alterations of mucosal gene-expression profiles in CRC-associated microbiota [22].…”

Mitochondrial Respiration in KRAS and BRAF Mutated Colorectal Tumors and Polyps

“…Normal cells exhibit only glycolytic and oxidative states [16][17][18]. Premalignant polyps and arising adenocarcinomas are still regarded as highly glycolytic tumors of the Warburg phenotype [19][20][21]. Previous studies indicate that although polyps have higher inclination to aerobic glycolysis, the metastatic carcinomas maintain high rates of O 2 consumption (much more than adjacent normal tissues) and exhibit obvious signs of stimulated mitochondrial biogenesis [6,[22][23][24].…”