Metabolic reprogramming in colorectal cancer: regulatory networks and therapy

Abstract

With high prevalence and mortality, together with metabolic reprogramming, colorectal cancer is a leading cause of cancer-related death. Metabolic reprogramming gives tumors the capacity for long-term cell proliferation, making it a distinguishing feature of cancer. Energy and intermediate metabolites produced by metabolic reprogramming fuel the rapid growth of cancer cells. Aberrant metabolic enzyme-mediated tumor metabolism is regulated at multiple levels. Notably, tumor metabolism is affected by nutrient levels, cell interactions, and transcriptional and posttranscriptional regulation. Understanding the crosstalk between metabolic enzymes and colorectal carcinogenesis factors is particularly important to advance research for targeted cancer therapy strategies via the investigation into the aberrant regulation of metabolic pathways. Hence, the abnormal roles and regulation of metabolic enzymes in recent years are reviewed in this paper, which provides an overview of targeted inhibitors for targeting metabolic enzymes in colorectal cancer that have been identified through tumor research or clinical trials.

Keywords: Colorectal cancer; Metabolic enzymes; Metabolic reprogramming; Signal transduction; Targeted therapy.

Fig. 1

Schematic of Glucose Metabolism with Metabolic Enzymes and Their Regulators in CRC Cells. Glucose metabolic pathways mainly consist of glycolysis, the PPP pathway, and the TCA cycle; Enzymes involved in the glucose metabolism process moonlighting functions and are adapted for survival or death; are shown. Brown boxes indicate metabolic enzymes. Blue boxes represent factors that alter glucose metabolism

Fig. 2

Amino Acid Metabolism in Cancer Cells and Its Crosstalk with Other Signal Pathways. Exogenous and endogenous amino acids are metabolized in CRC cells to fuel the unique biosynthetic and energetic requirements of the tumor, and metabolic enzymes involved in amino acid metabolism are regulated y different signals. Brown boxes indicate metabolic enzymes. Blue boxes represent factors that alter amino acid metabolism

Fig. 3

Dysregulation of Lipid Metabolism Pathways in CRC Cells and Their Metabolic Enzymes with Regulatory Networks. For de novo lipogenesis, CRC cells rely on glucose, glutamine, and acetate to synthesize acetyl-CoA. This is further catabolized by multiple enzymatic reactions to synthesize fatty acids and cholesterol, which provide a range of fatty acids to meet the cell requirements. In turn, excess fatty acids are oxidated to provide energy under stress conditions. Brown boxes indicate metabolic enzymes. Blue boxes represent factors that alter lipid metabolism

Fig. 4

Simplified Schematic of the De Novo Pyrimidine and Purine Synthesis Pathways in CRC Cells. Phosphoribose-1-pyrophosphate (PRPP) derived from the PPP pathway participates in the synthesis of pyrimidine and purine via distinct pathways with different substrates. Brown boxes indicate metabolic enzymes. Blue boxes represent factors that alter nucleotide metabolism