Altered metabolism in cancer: insights into energy pathways and therapeutic targets

Abstract

Cancer cells undergo significant metabolic reprogramming to support their rapid growth and survival. This study examines important metabolic pathways like glycolysis, oxidative phosphorylation, glutaminolysis, and lipid metabolism, focusing on how they are regulated and their contributions to the development of tumors. The interplay between oncogenes, tumor suppressors, epigenetic modifications, and the tumor microenvironment in modulating these pathways is examined. Furthermore, we discuss the therapeutic potential of targeting cancer metabolism, presenting inhibitors of glycolysis, glutaminolysis, the TCA cycle, fatty acid oxidation, LDH, and glucose transport, alongside emerging strategies targeting oxidative phosphorylation and lipid synthesis. Despite the promise, challenges such as metabolic plasticity and the need for combination therapies and robust biomarkers persist, underscoring the necessity for continued research in this dynamic field.

Keywords: Cancer metabolism; Glutaminolysis; Glycolysis; Lipid metabolism; Oxidative phosphorylation.

Fig. 1

This figure illustrates glycolysis as a key energy pathway in cancer cells, highlighting the pathway's steps from glucose to pyruvate, including all intermediate metabolites and enzymes (e.g., hexokinase, phosphofructokinase, pyruvate kinase). The roles of oncogenes and tumor suppressors in regulating glycolysis are indicated. The Warburg effect is highlighted by showing increased glycolytic flux and lactate production despite the presence of oxygen, with pyruvate diverted to lactate dehydrogenase instead of mitochondria. The contrast between glycolysis and oxidative phosphorylation in mitochondria is depicted, indicating the reduced reliance on mitochondrial metabolism in cancer cells. Potential therapeutic targets within the glycolytic pathway are showed, and suggestions for combining glycolytic inhibitors with other treatments are included. The clinical relevance is emphasized by showing how glycolytic metabolites or enzyme levels can serve as biomarkers for cancer diagnosis, with reference to 18F-fluorodeoxyglucose (FDG) PET imaging used for detecting high glycolytic activity in tumors

Fig. 2

This figure illustrates the role of Oxidative Phosphorylation (OXPHOS) in cancer metabolism, detailing key components, alterations, and therapeutic targets. The figure depicts the mitochondrial structure, including the electron transport chain (ETC) complexes I-IV and ATP synthase (Complex V), highlighting the flow of electrons from NADH and FADH2 to oxygen, producing water and ATP via chemiosmosis and the proton gradient. The figure also shows common cancer-associated alterations, such as the Warburg effect, mitochondrial dysfunction, and increased reactive oxygen species (ROS) production. Mutations in mtDNA genes can disrupt electron flow, leading to increased ROS production, which damages cellular components like DNA, proteins, and lipids, promoting further mutations and cancer progression. These mutations can also activate oncogenic signaling pathways such as NF-κB and HIF-1α. The bottom panel emphasizes therapeutic strategies, including ETC complex inhibitors, agents affecting mitochondrial biogenesis, and ROS modulation

Fig. 3

This figure illustrates glutaminolysis as a Key Energy Pathway in Cancer. Glutamine is transported into cancer cells and converted to glutamate by glutaminase (GLS). Glutamate is further converted to α-ketoglutarate (α-KG), entering the TCA cycle to support energy production. Glutaminolysis also replenishes TCA cycle intermediates and produces biosynthetic precursors for macromolecule synthesis. Additionally, it generates NADPH to maintain redox balance. Key enzymes in this pathway are potential therapeutic targets for cancer treatment

Fig. 4

This figure illustrates the comprehensive pathways of lipid metabolism in cancer cells, highlighting key processes such as lipid uptake, storage, fatty acid synthesis, β-oxidation, and cholesterol metabolism. Lipid uptake involves lipoprotein lipase (LPL), fatty acid transporters (FAT/CD36, FABP), and the formation of lipid droplets. Fatty acid synthesis is detailed from the conversion of citrate to acetyl-CoA, catalyzed by enzymes including ATP citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FASN), with regulation by stearoyl-CoA desaturase (SCD). The figure also depicts fatty acid oxidation (β-oxidation) within mitochondria and peroxisomes, mediated by carnitine palmitoyltransferase I (CPT1) and acyl-CoA dehydrogenases (ACAD). Cholesterol metabolism is shown, which can lead to the progression of cancer. Additionally, potential therapeutic targets and inhibitors, such as FASN and CPT1 inhibitors, are marked, underscoring their relevance in cancer treatment

Fig. 5

The figure illustrates the regulatory landscape of metabolic pathways in cancer, highlighting key influences from oncogenes (e.g., MYC, RAS) and tumor suppressor genes (e.g., p53, PTEN). Epigenetic modifications (DNA methylation, histone marks) are shown in the figure with its regulatory role. Microenvironmental factors such as hypoxia, nutrient availability (glucose, glutamine), and immune interactions are illustrated to impact metabolic adaptations in cancer cells. Interactions and feedback loops between these regulatory elements are represented, emphasizing how oncogene activation may enhance glycolysis and alter mitochondrial function, and how epigenetic silencing affects metabolic enzyme expression

Fig. 6

The flow chart illustrates the multifaceted challenges and future directions in overcoming metabolic plasticity in cancer cells. The left section highlights the primary challenges, including metabolic plasticity, metabolic heterogeneity within and between tumors, redundancy and compensation in metabolic pathways, influence of the tumor microenvironment and the difficulty in effectively targeting single metabolic pathways. The right section outlines future directions, such as comprehensive profiling of cancer metabolism at single-cell resolution using advanced omics technologies, targeting multiple pathways with combination therapies, modulating the tumor microenvironment to reduce metabolic adaptability, and understanding the temporal dynamics of metabolic changes to develop phase-specific therapies