The roles of glucose metabolic reprogramming in chemo- and radio-resistance

Abstract

Reprogramming of cancer metabolism is a newly recognized hallmark of malignancy. The aberrant glucose metabolism is associated with dramatically increased bioenergetics, biosynthetic, and redox demands, which is vital to maintain rapid cell proliferation, tumor progression, and resistance to chemotherapy and radiation. When the glucose metabolism of cancer is rewiring, the characters of cancer will also occur corresponding changes to regulate the chemo- and radio-resistance of cancer. The procedure is involved in the alteration of many activities, such as the aberrant DNA repairing, enhanced autophagy, oxygen-deficient environment, and increasing exosomes secretions, etc. Targeting altered metabolic pathways related with the glucose metabolism has become a promising anti-cancer strategy. This review summarizes recent progress in our understanding of glucose metabolism in chemo- and radio-resistance malignancy, and highlights potential molecular targets and their inhibitors for cancer treatment.

Keywords: Chemo-resistance; Metabolic reprogramming; Radio-resistance; TME.

Fig. 1

The energy metabolism of cancer cells. Under aerobic condition, Most of the glucose is first converted to pyruvate via glycolysis in the cytosol. Most pyruvate are mostly processed to lactate via glycolytic pyruvate even in the presence of oxygen, and only a small portion of pyruvates enters the mitochondria to produce CO₂ by undergoing TCA cycle. In addition, small proportion of the glucose is diverted into the upstream of pyruvate production for biosynthesis (e.g., pentose phosphate pathway, and amino acid synthesis)

Fig. 2

Simplified diagram of the main metabolic pathways involved in DNA damage/repair. Continuous activation of aerobic glycolysis can increase the capture of glucose into the cytoplasm by up-regulating the expression of glucose transporters (GLUTs) and substantially enhance the high rate of glucose influx via activating HK, PFK, and aldolase enzyme and promoting their expression, which in turn facilitates the aerobic glycolysis. The glycolytic switch in tumor cells allows the direct or indirect flux of glycolytic intermediates to many biosynthetic pathways (e.g., pentose phosphate pathway, serine synthesis pathway, MG pathway, and nucleotide synthesis), which provides the biomacromolecules and other materials required for prolonging the cancer cell survival via enhancing DNA repair, inhibiting DNA damage and decreasing chromatin remodeling

Fig. 3

The immunosuppressive effect of the tumor microenvironment. The hypoxia and acidosis of the tumor microenvironment (TME) contribute to immunosuppression via several mechanisms. These mechanisms include increased accumulation, activation, and expansion of immunosuppressive regulatory T (Treg) cells; recruitment of inflammatory monocytes and tumor-associated macrophages (TAMs) and reprogramming of TAMs towards the pro-tumor M₂ phenotype; suppression of dendritic cell (DC) maturation, which results in inhibiting activation of tumour-specific cytotoxic T lymphocytes (CTLs). Importantly, the programmed cell death protein 1 (PD-1)–programmed cell death 1 ligand 1 (PD-L1) pathway is often activated in the TME as a mechanism to evade anticancer immune responses, with up-regulation of PD-L1 expression on TAMs, DCs, and tumor cells. In addition, tumor-infiltrating CTLs typically up-regulate PD-1, limiting their cytotoxic potential against tumor cells. CCL20, C-C-motif chemokine ligand 20; CXCL, C-X-C-motif chemokine ligand; GM-CSF, granulocyte–macrophage colony-stimulating factor; TGFβ, transforming growth factor β; IL, Interleukin

Fig. 4

The role of the exosomes in the formation of CSCs. The cancer cells with enhanced glycolysis could release a large amount of exosomes contained several of glycolytic enzymes and CSCs markers. These exosomes can be taken up by the recipient cancer cells, and then promote the glycolysis and induce the dedifferentiation of cancer cells to acquire stemness phenotype through transfer their stemness-related molecules

Fig. 5

The overview of acquired chemoradiotherapy resistance mediated by metabolic reprogramming in cancer cells