Role of glucose metabolic reprogramming in colorectal cancer progression and drug resistance

Abstract

Colorectal cancer (CRC), with the incidence and mortality rising on a yearly basis, greatly threatens people's health. It is considered an important hallmark of tumorigenesis that aberrant glucose metabolism in cancer cells, particularly the Warburg effect. In CRC, the Warburg effect predominantly influences cancer development and progression via its involvement in the glycolytic pathway regarding cell metabolism. The critical mechanisms underlying this process include key glycolytic enzymes, transport proteins, regulatory molecules, and signaling pathways. Furthermore, targeting the reprogrammed glucose metabolism in cancer cells can be potentially used for CRC treatment. However, the mechanisms driving CRC onset and progression, especially in relation to glucose metabolism reprogramming, are not fully understood and represent an emerging field of research. The review aims at providing new insights into the role that glucose metabolism reprogramming plays in the progression of CRC progression together with its resistance to treatment. Ultimately, these insights strive to diminish the risks of CRC metastasis and recurrence.

Keywords: Aerobic glycolysis; Colorectal cancer; Glucose metabolism reprogramming; Warburg effect.

Graphical abstract

Fig 1

Glycolysis-related pathogenesis and therapy of CRC. Glycolysis promotes CRC progression and resistance to drugs by impacting key glycolytic enzymes (HK2, PFK, PKM2, LDH) and transport proteins (GLUT), regulatory molecules (P53, HIF-1α, c-MYC, and non-coding RNAs), and signaling pathways (PI3K/Akt, AMPK, MAPK, Wnt, STAT3, NF-κB, Hippo, β-catenin/c-Myc).

Fig 2

Glucose metabolism in CRC. Under aerobic conditions, glycolysis produces pyruvate, which fuels tricarboxylic acid (TCA) cycle after being converted to acetyl-CoA by mitochondria. That is accompanied by the generation of NADH and FADH2, driving OXPHOS for ATP synthesis. In hypoxia, glycolysis dominates, converting pyruvate to lactate, which is expelled from the cell. CRC cells primarily depend on glycolysis for energy, irrespective of oxygen levels. Tumorigenesis, metastasis, and drug resistance are promoted by this metabolic shift, even in the hypoxic TME.

Fig 3

Glycolysis and related regulatory pathways in CRC. Various signaling pathways influence the expression of pivotal regulatory genes via distinct mechanisms, contributing to like proliferation, invasion, migration and other malignant behaviors in CRC cells.