The Mechanism of Warburg Effect-Induced Chemoresistance in Cancer

Abstract

Although chemotherapy can improve the overall survival and prognosis of cancer patients, chemoresistance remains an obstacle due to the diversity, heterogeneity, and adaptability to environmental alters in clinic. To determine more possibilities for cancer therapy, recent studies have begun to explore changes in the metabolism, especially glycolysis. The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically, even under normoxia, which contributes to chemoresistance. However, the association between glycolysis and chemoresistance and molecular mechanisms of glycolysis-induced chemoresistance remains unclear. This review describes the mechanism of glycolysis-induced chemoresistance from the aspects of glycolysis process, signaling pathways, tumor microenvironment, and their interactions. The understanding of how glycolysis induces chemoresistance may provide new molecular targets and concepts for cancer therapy.

Keywords: Warburg effect; chemoresistance; signaling pathway; transporters and key enzymes of glycolysis; tumor microenvironment.

Figure 1

Glycolysis in cancer: cancer cells choose glycolysis as their primary energy source even under normoxia, which means pyruvate is mainly converted into lactate to play its role in energy source, rather than being incorporated into the TCA cycle. GLUT1 is responsible for transporting glucose, and MCTs are responsible for transporting lactate. ②, phosphohexose isomerase; ④, aldolase; ⑤, triose phosphate isomerase; ⑥, glyceraldehyde 3-phosphate dehydrogenase; ⑦, phosphoglycerate kinase; ⑧, phosphoglycerate mutase; ⑨, enolase.

Figure 2

Association between glycolysis transporter, key enzymes, and PI3K, HIF-1, C-MYC signaling pathways. PI3K, HIF-1, and C-MYC signaling pathways can activate the expression of key glycolysis enzymes and transporters to ensure cancer metabolism and energy supply; at the same time, the key enzymes and transporters of glycolysis can activate chemoresistance-related signaling pathways through their own or other protein mediators.

Figure 3

Association between Warburg effect-induced chemoresistance and tumor microenvironment. Tumor microenvironment undergoes a series of adjustments such as hypoxia, acidosis, and stromal cell formation to survival, which interact with glycolysis and oncogene PI3K, HIF-1 signaling pathways to induce chemoresistance in cancer.