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This poster explores critical pathways involved in metabolic reprogramming and regulation of cancer cell metabolism.
Updated August 29, 2023.
Altered cellular metabolism is a key characteristic of cancer cells, enabling them to increase the biosynthesis of essential macromolecules, maintain a permissive microenvironment, and cope with the increased production of reactive oxygen species (ROS)1. Drivers behind these changes include alterations in gene expression and key enzymes involved in glucose and glutamine metabolism2.
Insights into the mechanisms and regulation of cancer cell metabolism can provide the basis for developing improved anti-cancer drugs, therapeutic strategies, and biomarkers for diagnosis and prognosis. There is also an emerging need to better understand how inhibition of various metabolic pathways affects the tumor immune microenvironment, which can support or inhibit tumor growth3.
Glucose is a fundamental source of energy and essential building blocks for cells. Altered glucose metabolism in cancer cells is widely accepted central driver of malignancy, enabling tumor cells to meet the high energy demands required for growth and proliferation.
Under normal physiological conditions, healthy cells metabolize glucose to pyruvate through the glycolytic pathway. Pyruvate dehydrogenase then converts pyruvate to acetyl-CoA as fuel for the tricarboxylic acid (TCA) cycle—the metabolic engine that harvests energy for ATP production via oxidative phosphorylation.
Compared to normal differentiated cells, cancer cells dramatically increase glucose uptake and preferentially metabolize pyruvate (the end product of glycolysis) to lactate to extract energy instead of feeding it into the TCA cycle. The consequent lactate build-up creates an acidic environment that promotes tumor progression and metastasis. This well-known metabolic phenotype – the Warburg effect – occurs even in the presence of oxygen and functional mitochondria3.
Mechanisms involved in reprogramming glucose metabolism in cancer cells include the upregulation of glucose transporters (GLUTs) and overexpression of critical glycolytic enzymes, such as glyceraldehyde-3-phosphate dehydrogenase, enolase, and pyruvate kinase4. Consequently, many anti-cancer drugs target GLUTs and enzymes of the glycolytic pathway1,5.
In addition to driving cancer progression, altered glucose metabolism in cancer cells can affect responses to cancer treatment and contribute to drug resistance. For example, resistance to the chemotherapy drug paclitaxel has been linked to concerted upregulation of GLUTs, hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), and 6-Phosphofructo-2- kinase/fructose-2,6-bisphosphatase-3 (PFKFB3)5.
Glutamine metabolism is another pivotal pathway altered in cancer cells. All cells rely on glutamine as a carbon and nitrogen source for the biosynthesis of proteins, lipids, and nucleotides. Glutamine is also a precursor for the synthesis of the antioxidant glutathione, the TCA cycle intermediate α-ketoglutarate (α-KG), the excitatory neurotransmitter glutamate, and other biologically important molecules.
Depending on their oncogenotype and tissue of origin, cancer cells rewire glutamine metabolism in various ways to neutralize excess ROS generated by the TCA cycle, satisfy increased energy demands, and produce building blocks for synthesizing proteins, fatty acids, and nucleic acids. MYC and KRAS are among the many oncogenes known to modulate glutaminolysis and reprogramming of glutamine metabolism in cancer cells6.
Many cancer cells depend on glutamine for survival, consuming much higher levels of this amino acid relative to healthy cells. This "glutamine addiction" is often associated with enhanced glutamine uptake through transporters, such as SLC1A5, and overexpression of glutaminases, particularly the isoform GLS1, making these attractive targets for the development of small molecule drugs and other pharmacological strategies in cancer therapy7,9.
In cancer cells, the TCA cycle is often subverted to support the tumor's altered energetic and biosynthetic demands8. For instance, the TCA cycle can be rewired to generate increased levels of precursors required for nucleotide and amino acid synthesis, which are essential for tumor cell growth and proliferation.
Emerging evidence suggests that cancer cells may possess a degree of metabolic plasticity, making them more or less reliant on the TCA cycle and mitochondrial respiration for energy production and synthesis of certain macromolecules.7 Understanding the mechanisms underlying this plasticity may support the development of novel treatments and personalized therapies.7
Apart from their metabolic function, TCA cycle metabolites also play non-metabolic signaling roles in controlling cell function and fate and have been implicated in immunity and tumor malignancy9. For example, TCA intermediates, such as succinate and fumarate, are well-known as oncometabolites involved in tumorigenesis10,11.
What to expect from our poster
Explore our cancer metabolism poster for a deeper look into how glucose and glutamine are metabolized in cancer cells to allow for the biosynthesis of macromolecules and to meet energy requirements for rapid cell proliferation.