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Cancer metabolism; Glycolysis; Pentose phosphate pathway; Amino acid metabolism; Lipid metabolism; Mitochondrial function; Therapeutic targets

Introduction

The aberrant metabolic phenotype of cancer cells has been recognized for decades as a hallmark of cancer. Otto Warburg first observed enhanced glycolysis in cancer cells even in the presence of oxygen, known as the Warburg effect. Since then, extensive research has revealed that cancer cells undergo widespread metabolic reprogramming to support their rapid proliferation and survival [1]. Metabolic pathways not only provide energy but also generate biomass necessary for cell growth and division. This review examines how dysregulated metabolic pathways contribute to cancer cell proliferation and discusses emerging therapeutic strategies targeting these pathways [2].

Glycolysis and cancer cell proliferation

Glycolysis, a fundamental metabolic pathway, converts glucose to pyruvate and generates ATP and intermediates for biosynthesis. Cancer cells often exhibit increased glycolytic flux, even under aerobic conditions, which is essential for providing rapid ATP production and metabolic intermediates for macromolecule synthesis [3]. This metabolic adaptation supports the high energy demands and biosynthetic requirements of proliferating cancer cells. Key enzymes involved in glycolysis, such as hexokinase, phosphofructokinase, and pyruvate kinase, are frequently dysregulated in cancer, promoting glycolytic flux and tumor growth.

The pentose phosphate pathway (PPP) in cancer

The PPP branches off from glycolysis and plays a crucial role in generating ribose-5-phosphate for nucleotide synthesis and NADPH for redox homeostasis. Cancer cells often upregulate the PPP to support nucleic acid and lipid biosynthesis, as well as to counteract oxidative stress [4, 5]. Dysregulated expression of PPP enzymes, such as glucose-6-phosphate dehydrogenase (G6PD), enhances cancer cell proliferation and contributes to drug resistance. Targeting the PPP has emerged as a potential therapeutic strategy to exploit metabolic vulnerabilities in cancer cells.

Amino acid metabolism in cancer

Amino acids are not only building blocks for proteins but also key regulators of cellular metabolism. Cancer cells rewire amino acid metabolism to fuel growth and proliferation. For instance, serine and glycine metabolism is crucial for nucleotide synthesis, while glutamine metabolism supports energy production and redox balance [6]. Alterations in amino acid transporters and enzymes involved in amino acid metabolism are frequently observed in cancer, highlighting their role in sustaining rapid cell proliferation and tumor progression.

Lipid metabolism and cancer cell signaling

Lipids serve as structural components of cell membranes and signaling molecules in cancer cells. Lipid metabolism is dysregulated in cancer to support membrane synthesis, energy storage, and signaling pathways that promote cell proliferation and survival. Enhanced de novo lipogenesis mediated by enzymes like fatty acid synthase (FASN) is a common feature of many cancers and correlates with poor prognosis. Targeting lipid metabolism offers new avenues for therapeutic intervention in cancer treatment [7,8].

Mitochondrial function and metabolic reprogramming

Mitochondria play a central role in energy metabolism, oxidative phosphorylation, and cellular signaling. In cancer, mitochondrial function is often altered to support metabolic reprogramming and tumor growth. Mitochondrial dynamics, biogenesis, and respiratory capacity are dysregulated in cancer cells, leading to increased reliance on glycolysis and altered redox balance. Mitochondria-targeted therapies aim to exploit these metabolic vulnerabilities and sensitize cancer cells to treatment [9].

Therapeutic targeting of metabolic pathways

Exploiting the metabolic dependencies of cancer cells has emerged as a promising therapeutic strategy. Small molecule inhibitors targeting glycolysis, PPP, amino acid metabolism, lipid metabolism, and mitochondrial function are under investigation in preclinical and clinical settings [10]. Combination therapies that simultaneously target multiple metabolic pathways aim to overcome drug resistance and improve treatment efficacy. Precision medicine approaches, guided by metabolic profiling of tumors, offer personalized treatment options based on individual metabolic vulnerabilities.

Conclusion

Metabolic reprogramming is a hallmark of cancer cells, supporting their rapid proliferation and survival in nutrient-deprived tumor microenvironments. Dysregulated glycolysis, PPP, amino acid metabolism, lipid metabolism, and mitochondrial function provide numerous targets for therapeutic intervention. Understanding the complex interplay of these metabolic pathways in cancer biology is essential for developing effective treatments that exploit metabolic vulnerabilities while minimizing systemic toxicity. Future research efforts will continue to elucidate the intricate metabolic networks driving cancer cell proliferation, paving the way for innovative therapies and improved patient outcomes.

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