The Role of Central Carbon Metabolism in Cancer

Central carbon metabolism involves a network of biochemical pathways responsible for the conversion of glucose, fatty acids, and amino acids into ATP and key metabolic intermediates. In cancer, central carbon metabolism is often rewired to meet the increased energy demands of rapidly dividing cells. This metabolic shift is crucial for fueling cell growth and providing building blocks for macromolecules such as DNA, RNA, and proteins. Reprogramming of central carbon pathways is a hallmark of cancer, enabling tumor cells to survive in hypoxic, nutrient-limited environments.

Otto Warburg's pioneering work in the 1920s identified a key feature of cancer metabolism: cancer cells tend to rely on glycolysis, even in the presence of oxygen, a phenomenon now known as the Warburg effect. This observation led to a paradigm shift in how we understand the metabolic demands of cancer cells. Warburg's discovery highlighted the role of glycolysis in supporting rapid cell proliferation and provided a foundation for further exploration into cancer cell metabolism.

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Central Carbon Metabolism Pathways in Cancer

Glycolysis and the Warburg Effect

Glycolysis, the breakdown of glucose to produce pyruvate, is a central metabolic pathway. In cancer, this process is often upregulated, even when oxygen is present, resulting in increased lactate production. This metabolic shift allows for faster ATP production and the generation of intermediates necessary for biosynthetic processes. The Warburg effect is integral to cancer cell survival, providing not only energy but also metabolic intermediates required for rapid growth and division. Furthermore, lactate production contributes to tumor acidification, creating an environment that promotes immune evasion and metastasis.

The TCA Cycle and Anaplerotic Pathways

The tricarboxylic acid (TCA) cycle plays a central role in cellular metabolism by generating ATP and key intermediates for biosynthesis. In cancer cells, the TCA cycle is often altered. Mutations in enzymes like succinate dehydrogenase (SDH) and isocitrate dehydrogenase (IDH) lead to the accumulation of oncometabolites such as 2-hydroxyglutarate, which can promote tumorigenesis through epigenetic modifications. Additionally, cancer cells frequently utilize anaplerosis, a process where intermediates like glutamine replenish the TCA cycle, ensuring its continuous function even when glucose is scarce.

Oxidative Phosphorylation (OXPHOS)

While glycolysis is favored in many cancer cells, OXPHOS remains an important energy-generating process. OXPHOS occurs in the mitochondria and contributes to ATP production through the oxidation of NADH and FADH2 generated from the TCA cycle. In some cancers, OXPHOS activity is enhanced, particularly under conditions of high metabolic demand or during cellular adaptation to stress. The balance between glycolysis and OXPHOS varies by cancer type and progression stage, and targeting this balance offers therapeutic potential.

The Pentose Phosphate Pathway (PPP)

The PPP is a parallel pathway to glycolysis that serves as a critical source of ribose-5-phosphate for nucleotide synthesis and NADPH for maintaining cellular redox balance. Cancer cells often exhibit increased PPP activity to support their anabolic demands and to protect against oxidative stress. Enhanced nucleotide biosynthesis enables rapid cell proliferation, while elevated NADPH levels help to neutralize reactive oxygen species (ROS) that accumulate due to high metabolic activity.

Amino Acid Metabolism

Amino acids are central to cancer cell metabolism, serving as precursors for proteins, nucleotides, and TCA cycle intermediates. Cancer cells often exhibit altered amino acid metabolism to support their growth. Glutamine, for instance, is a key fuel source that feeds into the TCA cycle, providing intermediates for energy production and biosynthesis. Similarly, serine and glycine are critical for one-carbon metabolism, which supports nucleotide synthesis and epigenetic modifications crucial for tumor growth and survival.

Central carbon metabolism in cancer (Sidorkiewicz et al., 20223).

Key Oncogenic Pathways Affecting Central Carbon Metabolism

Activation of Oncogenes (e.g., MYC, RAS)

MYC and Glucose Metabolism

MYC is a key oncogene that drives metabolic reprogramming in cancer cells. It upregulates enzymes involved in glycolysis, such as HK2 (hexokinase 2), LDHA (lactate dehydrogenase A), and PKM2 (pyruvate kinase M2), enhancing glucose consumption and lactate production, a hallmark of the Warburg effect. MYC also promotes glutamine utilization, fueling the TCA cycle and biosynthesis. This dual activation of glucose and glutamine metabolism helps cancer cells meet the high demands for energy and building blocks for macromolecular synthesis, supporting rapid proliferation.

RAS and Metabolic Reprogramming

RAS oncogenes (KRAS, NRAS, HRAS) are commonly mutated in cancers like pancreatic, lung, and colorectal cancer. Activated RAS enhances glycolysis by upregulating glucose transporters and key glycolytic enzymes. It also promotes glutamine metabolism, similar to MYC, by increasing the uptake and conversion of glutamine to TCA intermediates, which are crucial for energy production and biosynthesis. RAS mutations also alter mitochondrial dynamics, shifting the balance away from oxidative phosphorylation (OXPHOS) toward glycolysis, further supporting the Warburg effect.

Tumor Suppressor Gene Loss (e.g., p53)

Loss of p53 and Its Impact on Metabolism

p53, a key tumor suppressor, normally restricts glycolysis and promotes oxidative metabolism by enhancing mitochondrial function. In p53-deficient cancers, this balance is disrupted. The loss of p53 function leads to an upregulation of glycolysis, even in the presence of oxygen, driving the Warburg effect. This shift allows tumor cells to quickly generate ATP and biosynthetic intermediates required for rapid cell division.

Mitochondrial Dysfunction in p53-Deficient Tumors

Without functional p53, mitochondrial function is compromised. The loss of p53 reduces oxidative phosphorylation and promotes mitochondrial dysfunction, further driving the glycolytic switch. Additionally, the accumulation of reactive oxygen species (ROS) due to mitochondrial dysfunction can contribute to genetic instability, further supporting tumor progression and survival.

Hypoxia-Inducible Factor (HIF)

HIF and Adaptation to Hypoxia

Under hypoxic conditions, HIF-1α is stabilized and activates genes that promote glycolysis, including HK2, LDHA, and PKM2, ensuring cancer cells can continue to generate ATP through anaerobic pathways. HIF also promotes angiogenesis by increasing the expression of VEGF, which supports tumor growth by providing additional oxygen and nutrients. These metabolic and structural adaptations enable cancer cells to survive and proliferate in low-oxygen environments.

Role of HIF in Tumor Growth

HIF-mediated metabolic reprogramming allows tumors to thrive in hypoxic areas where oxygen and nutrient supply is limited. By enhancing glycolysis and promoting angiogenesis, HIF ensures that cancer cells can continue growing even when oxygen levels are insufficient for normal cellular respiration. This adaptive response contributes to tumor progression and metastasis.

Impact of Central Carbon Metabolism on Tumor Microenvironment

Acidification of the Tumor Microenvironment

Cancer cells, due to their reliance on glycolysis even under normoxic conditions (the Warburg effect), produce large amounts of lactate as a byproduct, which is exported into the extracellular space. The accumulation of lactate and protons in the TME leads to significant acidification, typically lowering the pH to values as low as 6.0–6.5, compared to the normal pH of 7.4 in healthy tissues. This low pH directly impacts tumor progression and immune responses.

The acidification of the TME facilitates cancer cell survival and metastasis by promoting processes such as angiogenesis, cell motility, and invasion. A more acidic environment activates matrix metalloproteinases (MMPs), enzymes that degrade the extracellular matrix (ECM) and facilitate the invasion of tumor cells into surrounding tissues. Furthermore, acidification also suppresses immune cell function, impairing the ability of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells to effectively recognize and kill tumor cells.

In addition to immune suppression, low pH can also promote epithelial-to-mesenchymal transition (EMT), a process where epithelial cancer cells acquire migratory and invasive properties, aiding in metastasis. The acidified TME creates a favorable niche for tumor cells to survive, proliferate, and disseminate, making it a critical factor in cancer progression.

Nutrient Competition and Cancer Cell Growth

In the TME, cancer cells compete with surrounding stromal cells (e.g., fibroblasts, endothelial cells, and immune cells) for limited nutrients, such as glucose, glutamine, and oxygen. Cancer cells typically exhibit increased glucose uptake and glutamine consumption, prioritizing these nutrients to support enhanced glycolysis and biosynthetic demands. In contrast, non-cancerous stromal cells, which rely more heavily on oxidative phosphorylation, face nutrient depletion as the tumor mass expands.

The competition for resources within the TME impacts not only tumor growth but also tumor progression and metastasis. Cancer cells, with their altered metabolism, can adapt by switching between available nutrient sources, a process known as metabolic flexibility. In particular, glutamine metabolism becomes critical, as it supports both the TCA cycle and biosynthetic pathways. Moreover, the metabolic changes of cancer cells can indirectly affect stromal cell metabolism, potentially leading to reprogramming of stromal fibroblasts and endothelial cells in ways that support tumor growth and angiogenesis.

Immune Evasion and Modulation

Metabolic reprogramming in cancer cells also influences immune cell function, contributing to immune evasion. Tumors often induce T cell exhaustion and promote macrophage polarization, both of which diminish the immune system's ability to detect and eliminate cancer cells.

T cell exhaustion occurs when metabolic byproducts, such as lactate and low pH, accumulate in the TME, leading to impaired T cell activation, proliferation, and function. High lactate concentrations inhibit T cell receptor signaling, reducing the cytotoxic activity of CD8+ T cells and impairing their ability to kill tumor cells. Similarly, the low pH environment affects the function of T helper cells (Th1), which are essential for coordinating immune responses against tumors.

The TME also induces the polarization of macrophages from an anti-tumor, M1 phenotype to a pro-tumor, M2 phenotype. This shift is driven by metabolic changes, particularly by the increased availability of fatty acids and lactate, which promote M2 macrophage polarization. M2 macrophages support tumor growth by secreting immunosuppressive cytokines, promoting angiogenesis, and aiding in tissue remodeling, all of which contribute to tumor progression and immune escape.

Together, the metabolic reprogramming of both tumor and stromal cells creates an immunosuppressive environment that allows tumors to evade immune detection and continue to grow and metastasize.

Metabolic Reprogramming and Therapy Resistance

Resistance to Chemotherapy

Central carbon metabolism plays a crucial role in chemotherapy resistance. The Warburg effect, where cancer cells preferentially rely on glycolysis for ATP production even in the presence of oxygen, helps maintain rapid biosynthesis of macromolecules. However, this also leads to lactate accumulation, acidifying the tumor microenvironment, which helps cancer cells evade chemotherapy-induced cytotoxicity and enhances cell survival.

In addition, increased glutamine metabolism provides critical intermediates for the TCA cycle, replenishing energy and supporting redox balance under oxidative stress. The metabolic shift towards glutaminolysis allows cells to continue growth and proliferation even under chemotherapy-induced stress, while the upregulation of multidrug resistance (MDR) transporters can actively efflux chemotherapeutic agents, reducing their efficacy.

These metabolic adaptations enable cancer cells to bypass chemotherapy-induced damage and maintain survival in a hostile environment.

Metabolic Reprogramming and Targeted Therapy Resistance

Central carbon metabolism also influences resistance to targeted therapies, such as those against EGFR (epidermal growth factor receptor) or HER2 (human epidermal growth factor receptor 2). Tumor cells often rely on metabolic reprogramming to overcome inhibition of these oncogenic pathways. Glutamine metabolism plays a key role in sustaining resistance by fueling the TCA cycle and supporting anabolic processes, even in the presence of EGFR or HER2 inhibition.

Glutaminolysis, which increases in many cancers, replenishes TCA intermediates, allowing tumors to bypass glycolytic limitations. Simultaneously, the pentose phosphate pathway (PPP) is often upregulated, providing ribose-5-phosphate for nucleotide synthesis and NADPH for redox balance, both crucial for continued cell growth and DNA repair in response to targeted therapy-induced stress.

Additionally, oxidative phosphorylation and mitochondrial metabolism remain active in therapy-resistant tumors, ensuring energy production even when key signaling pathways are blocked. Activation of the PI3K-AKT-mTOR pathway further promotes glycolysis, supporting cancer cell survival and resistance.

Cellular and Non-cellular Factors Mediating Intratumor Heterogeneity (Pranzini et al., 2021).

Targeting Central Carbon Metabolism in Cancer Therapy

Metabolic Inhibitors

Metabolic inhibitors targeting central carbon metabolism are being actively explored as potential cancer therapies.

• Glycolysis Inhibitors: Given the Warburg effect, cancer cells often exhibit increased reliance on glycolysis, even in the presence of oxygen. Several inhibitors targeting glycolytic enzymes are under investigation, including 2-deoxyglucose (2-DG), which inhibits hexokinase and glucose transporters, thereby blocking glycolysis. Other promising candidates are GSK923295, which targets pyruvate kinase M2 (PKM2), and oxamate, which inhibits lactate dehydrogenase A (LDHA). By impeding glycolysis, these inhibitors aim to starve the tumor cells of energy and biosynthetic precursors.
• Oxidative Phosphorylation (OXPHOS) Inhibitors: Cancer cells can also switch to oxidative phosphorylation for energy production under certain conditions, particularly in high-oxygen environments or in certain tumor types. Inhibitors of complex I of the mitochondrial respiratory chain, such as metformin, have shown promise in preclinical models of cancer. IACS-010759, a novel complex I inhibitor, has demonstrated the ability to reduce OXPHOS and induce cancer cell apoptosis. Inhibiting mitochondrial function may prevent tumor cells from using the electron transport chain (ETC) for energy production, forcing them to rely on less efficient and more vulnerable pathways.
• Glutamine Metabolism Inhibitors: Glutamine is a crucial metabolite for cancer cells, providing both energy and biosynthetic precursors. Inhibitors of glutaminase, the enzyme that converts glutamine to glutamate, have been explored as potential therapies. CB-839, an orally bioavailable glutaminase inhibitor, has shown efficacy in preclinical studies and is currently undergoing clinical trials. Targeting glutamine metabolism can disrupt tumor cell growth by depriving them of critical metabolic intermediates required for macromolecule synthesis and mitochondrial function.

Combination Therapies

Combination with Chemotherapy: Combining metabolic inhibitors with conventional chemotherapy can sensitize cancer cells to the effects of cytotoxic drugs. For example, glycolysis inhibitors like 2-DG or LDHA inhibitors can enhance the cytotoxicity of chemotherapeutic agents such as cisplatin or doxorubicin by disrupting energy production and increasing oxidative stress within the tumor. These inhibitors can also reduce the tumor's ability to repair chemotherapy-induced DNA damage, improving therapeutic outcomes.

Combination with Immunotherapy: Targeting central carbon metabolism can also enhance the effectiveness of immunotherapy. Tumor cells often exploit metabolic pathways to suppress immune cell function and evade immune surveillance. By inhibiting glycolysis or glutamine metabolism, metabolic inhibitors can restore immune cell function, enhancing the efficacy of immune checkpoint inhibitors (e.g., anti-PD-1, anti-CTLA-4) or adoptive T cell therapies. For instance, inhibition of glycolysis has been shown to enhance T cell activation and prevent T cell exhaustion, improving the response to immunotherapies.

Targeting Metabolic Vulnerabilities: Combination approaches may also exploit specific metabolic vulnerabilities of cancer cells. For example, combining glutamine metabolism inhibitors with autophagy inhibitors could prevent cancer cells from compensating for metabolic stress, leading to enhanced tumor cell death. Additionally, combining OXPHOS inhibitors with radiation therapy can limit the energy production available to cancer cells during radiation-induced DNA damage, making them more susceptible to treatment.

While combination therapies show promise, challenges remain, including the identification of optimal drug combinations, potential toxicity, and the risk of metabolic reprogramming leading to therapy resistance. Further research is needed to refine these strategies and improve patient outcomes.

Biomarkers of Metabolic Dysregulation

• Metabolite Profiling: Metabolite profiling through mass spectrometry and NMR spectroscopy can identify specific metabolites that are dysregulated in cancer, such as lactate, pyruvate, glutamine, and various TCA cycle intermediates. Elevated levels of lactate or glutamine may serve as biomarkers of increased glycolysis or glutamine dependency, respectively, indicating that metabolic inhibitors targeting these pathways could be effective in treating these tumors.
• Gene Expression Markers: The expression of key enzymes involved in central carbon metabolism, such as hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), and glutaminase, can also serve as biomarkers for tumor metabolism. Elevated expression of these enzymes correlates with poor prognosis in various cancers and could help identify patients who may benefit from metabolic inhibitors.
• Imaging Biomarkers: Non-invasive imaging techniques, such as positron emission tomography (PET) using labeled glucose analogs like 18F-FDG, can provide insights into the metabolic activity of tumors. Changes in glucose uptake and oxygen consumption can be tracked to assess the effectiveness of metabolic therapies and predict patient response.

References

1. Sidorkiewicz, Iwona, et al. "Identification and subsequent validation of transcriptomic signature associated with metabolic status in endometrial cancer." Scientific Reports 13.1 (2023): 13763.
2. Pranzini, Erica, et al. "Metabolic reprogramming in anticancer drug resistance: a focus on amino acids." Trends in Cancer 7.8 (2021): 682-699.