Amino acids play a crucial role in the proliferation of mammalian cells, particularly in cancerous tissues where there is a heightened demand for these essential building blocks for protein synthesis. The distinction between essential and non-essential amino acids becomes pivotal in understanding how cancer cells balance their supply and demand within a tumor microenvironment.
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Non-Essential Amino Acids: A Hidden Requirement
While traditionally considered non-essential, certain amino acids become essential for specific cancers due to the loss of expression of key enzymes involved in their synthesis. For example, arginine, synthesized by argininosuccinate synthetase (ASS1), is deficient in various malignancies, leading to trials of arginine deiminase (ADI) as a potential cancer therapy. Silencing of asparagine synthetase (ASNS) in certain cancers establishes the importance of exogenous asparagine, exploited in the successful treatment of pediatric acute lymphoblastic leukemia with bacterial asparaginase. Glutamine, regulated by glutamine synthetase (GS), emerges as another non-essential amino acid crucial for tumor growth in specific cancers.
The Aspartate Hub: A Metabolic Keystone
Aspartate, a significant hub in amino acid metabolism, is central to synthesizing other amino acids and anabolic pathways, such as purine and pyrimidine synthesis. Tumors may prioritize nucleotide synthesis over asparagine and arginine production, potentially leading to aspartate depletion in specific tumor types. Interestingly, resistance mechanisms, such as autophagy, may temporarily counteract therapeutic interventions targeting amino acid depletion, emphasizing the complexity of cancer cell survival strategies.
Metabolic Relationship Between Tumor and Stroma
The exchange of metabolites, particularly amino acids, is crucial in tumor metabolism. A bidirectional relationship is noted between cancer-associated fibroblasts (CAFs) and cancer cells, where CAFs provide aspartate to support cancer cell nucleotide biosynthesis, and cancer cells reciprocate with glutamate. This metabolic collaboration potentially reduces cancer cells' reliance on the oxidative TCA cycle, altering nutrient profiles and oxygen consumption. Gliomas demonstrate the importance of the amido group of glutamine for purine synthesis and nucleotide synthesis. Additionally, macropinocytosis allows cancer cells to engulf microenvironmental proteins, sustaining proliferation in nutrient-poor conditions. Tumors exploit diverse mechanisms, including extracellular matrix-derived amino acids, for malignant progression. Targeting these mechanisms for therapy requires precision due to their reliance on physiological processes, minimizing on-target side effects.
Fig. 1 Metabolism of glutamine (Vettore L., et al. 2020).
Regulation of Amino Acid Synthetic Pathways
The regulation of non-essential amino acid synthesis involves a complex interplay between various metabolic pathways. The reversible transamination reactions, primarily using glutamate as an amino donor, connect amino acid synthesis with redox homeostasis. Amino acid synthesis is intricately linked to the tricarboxylic acid (TCA) cycle, malate-aspartate shuttle, and mitochondrial redox dynamics, underscoring the interconnectedness of these pathways. Examples like alanine and proline synthesis highlight the adaptive strategies employed by cancer cells to modulate amino acid production based on the cellular redox state and metabolic demands.
Non-Proteinogenic Amino Acids: The Overlooked Players
Beyond proteinogenic amino acids, non-proteinogenic amino acids play crucial roles in cancer metabolism. Taurine, β-alanine, and δ-aminolevulinic acid are non-proteinogenic amino acids with potential implications in tumorigenesis. Their roles, however, remain understudied, highlighting a gap in current research methodologies that often neglect these metabolites present in physiological concentrations.
A comprehensive understanding of amino acid metabolism in cancer unveils a sophisticated network where cancer cells dynamically adapt to varying nutrient availabilities. The intricate interactions between tumor and stroma, the regulatory mechanisms governing amino acid synthesis, and the roles of non-proteinogenic amino acids all contribute to the complex landscape of cancer metabolism. As research methodologies evolve to encompass more physiologically relevant conditions, including diverse media compositions, the translational potential of targeting amino acid metabolism in cancer therapy becomes more promising. Ultimately, deciphering the nuances of amino acid metabolism offers new avenues for developing targeted interventions to disrupt tumor growth and improve patient outcomes.
Reference
- Vettore L., et al. New aspects of amino acid metabolism in cancer. British Journal of Cancer. 2020, 122(2): 150-156.
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