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Targeting the Warburg Effect in Cancer: Where Do We Stand? - PubMed

  • ️Mon Jan 01 2024

Review

Targeting the Warburg Effect in Cancer: Where Do We Stand?

Ignasi Barba et al. Int J Mol Sci. 2024.

Abstract

The Warburg effect, characterized by the preferential conversion of glucose to lactate even in the presence of oxygen and functional mitochondria, is a prominent metabolic hallmark of cancer cells and has emerged as a promising therapeutic target for cancer therapy. Elevated lactate levels and acidic pH within the tumor microenvironment (TME) resulting from glycolytic profoundly impact various cellular populations, including macrophage reprogramming and impairment of T-cell functionality. Altogether, the Warburg effect has been shown to promote tumor progression and immunosuppression through multiple mechanisms. This review provides an overview of the current understanding of the Warburg effect in cancer and its implications. We summarize recent pharmacological strategies aimed at targeting glycolytic enzymes, highlighting the challenges encountered in achieving therapeutic efficacy. Additionally, we examine the utility of the Warburg effect as an early diagnostic tool. Finally, we discuss the multifaceted roles of lactate within the TME, emphasizing its potential as a therapeutic target to disrupt metabolic interactions between tumor and immune cells, thereby enhancing anti-tumor immunity.

Keywords: Warburg effect; aerobic glycolysis; immunomodulation; tumor metabolism; tumor microenvironment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1

Schematic representation of the metabolic fate of glucose in a tumoral cell. Warburg effect or aerobic glycolysis involves the conversion of glucose into pyruvate and subsequently into lactate, despite cancer cells possessing a fully functional respiratory chain. Enhanced glycolytic pathway not only results in increased lactate and proton secretion to the extracellular compartment but also increases the availability of glycolysis intermediates. This fact allows the increased flow of substrates to the pentose phosphate pathway (PPP) and one-carbon cycle, promoting nucleotide and lipid synthesis and maintaining redox homeostasis. (1,3-biPG: 1,3-biphosphoglycerate; 2-PG: 2-phosphoglicerate; 3-PG: 3-phosphoglicerate; ADP: adenosine diphosphate; aKG: alpha-ketoglutarate; ALDO: aldolase; ATP: adenosine triphosphate; DHAP: dihydroxyacetone phosphate; ENO: enolase; FAD+: flavin adenine dinucleotide; G6PD: glucose-6-phosphate dehydrogenase; GA3P: glyceraldehyde 3-phosphate; GAPDH: glyceraldehyde 3-phosphate; GDP: Guanosine diphosphate; GLUT1: glucose transporter 1; GSH: glutathione; GTP: Guanosine triphosphate; HCy: homocysteine; HK: hexokinase, LDH: lactate dehydrogenase; MCT4: monocarboxylate transporter 4; Met: methionine; NAD+: nicotinamide adenine dinucleotide; NADP: nicotinamide adenine dinucleotide phosphate; OAA: oxaloacetic acid; PEP: phosphoenolpyruvate; PFK: phosphofructokinase; PGAM: phosphoglycerate mutase; PGI: phosphoglucoisomerase; PGK: phosphoglycerate kinase; PK: pyruvate kinase; SucCoa: succinyl-coA; THF: Tetrahydrofolate).

Figure 2
Figure 2

The impact of the Warburg effect on the tumor microenvironment. Tumor microenvironment (TME) is composed of different cell types, including tumor, stromal, and immune cells. Increased lactate secretion and acidification remodel these TME populations in favor of tumor progression, angiogenesis, and immunosuppression. Tumor cells and cancer-associated fibroblasts (CAFs) secrete lactate into the media, which in turn can be used by the tumor to meet energy and intermediate product requirements. This phenomenon is known as the reverse Warburg effect. Lactate and acidosis have been described to modulate the phenotype and functionality of several components of the innate and adaptative immune system, inhibiting the proliferation and cytotoxic activity of T-cells and natural killer (NK) cells as well as reducing the differentiation of dendritic cells. In contrast, regulatory T-cells (Tregs) are less sensitive to high lactate concentrations and can maintain their immunosuppressive role. Furthermore, lactate promotes the polarization of tumor-associated macrophages (TAMs) towards a pro-tumoral phenotype, thereby promoting tumor growth and invasion. (GLUT: glucose transporter; IL6: interleukine-6; INF-y: interferon-gamma; MCT1/4: monocarboxylate transporter 1/4; PD1: programmed cell death protein 1).

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