Metabolism | Project 29

Cancer breathes.

Cancer needs energy, building blocks for growth, and checkpoint elimination.

Cellular Metabolism

Cancer cells have unique metabolic requirements and behaviors compared to normal cells. They typically undergo a phenomenon known as the Warburg Effect, wherein even in the presence of ample oxygen, cancer cells tend to favor aerobic glycolysis over oxidative phosphorylation.

Aerobic Glycolysis

Warburg Effect

Aerobic glycolysis, often referred to as the Warburg effect, is a phenomenon where cancer cells preferentially use glycolysis to produce energy, even in the presence of sufficient oxygen. Normally, cells would use oxidative phosphorylation, a more efficient way of generating ATP – but there are advantages in aerobic glycolysis.

Rapid Energy Production

Glycolysis provides quicker access to ATP, which is crucial for fast-growing cancer cells.

Biosynthetic Precursors

Glycolysis produces important intermediates needed for synthesizing nucleotides, amino acids, and lipids, which are essential for rapid cell division.

Reduced Oxidative Stress

Less reliance on oxidative phosphorylation can reduce the production of reactive oxygen species (ROS). At low to moderate levels, ROS acts as signaling transducers to activate cancer cell proliferation, migration, invasion, angiogenesis, and drug resistance.

Role of Copper

In Aerobic Glycolysis

Copper indirectly influences aerobic glycolysis through its involvement in several key enzymes and pathways:

Enzyme Activity

Cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain, needs copper. While this might seem counterintuitive since aerobic glycolysis reduces the reliance on oxidative phosphorylation, copper's role in energy production is still crucial. Efficient mitochondrial function (even at reduced capacity) is necessary to support the energy needs of rapidly dividing cells, and any mitochondrial activity can help sustain the high glycolytic rate.

Superoxide dismutase (SOD), which helps mitigate oxidative stress, needs copper. By managing ROS levels, SOD helps maintain cellular integrity, allowing cancer cells to survive and proliferate even under metabolic stress conditions.

Regulation of HIFs

Hypoxia-inducible factors (HIFs), transcription factors involved in cellular response to oxygen availability, are influenced by copper. HIFs promote the expression of genes involved in glycolysis and angiogenesis. Under hypoxic (low oxygen) conditions, or even in normoxic conditions within tumors, HIFs can drive the expression of glycolytic enzymes, thus enhancing the glycolytic pathway favored by cancer cells.

Angiogenesis

While not directly involved in glycolysis, copper’s role in angiogenesis supports the metabolic demands of cancer cells. By promoting the formation of new blood vessels, copper ensures a steady supply of oxygen and nutrients, which can be crucial even for glycolytically favored cancer cells to sustain their rapid growth.

Stable Isotopes of Copper

Stable isotopes of copper are non-radioactive forms of copper that differ in their number of neutrons but share the same number of protons. Copper has two stable isotopes, copper-63 (63Cu) and copper-65 (65Cu), which are naturally found in the environment and in biological systems.

Copper-63 (63Cu):

Natural Abundance: ~ 69.17%

Neutrons: 34 (29 protons + 34 neutrons)

Copper-65 (65Cu):

Natural Abundance: ~ 30.83%

Neutrons: 36 (29 protons + 36 neutrons)

Understanding Isotopic Fractionation

Isotopic fractionation refers to changes in the relative abundances of copper isotopes due to cancer processes. These changes can be subtle, but measurable using advanced technology, affecting the relative concentration of the two stable isotopes, copper-63 and copper-65.

Project-29 investigates how the stable isotopes of copper may change due to isotopic fractionation.

Differential Uptake: Cancer altered metabolic processes affect the uptake and utilization of copper leading to preferentially incorporate one isotope over another.

Enzymatic Utilization: As the enzymatic activities are altered in cancer cells, this affects how isotopes of copper are used, leading to a measurable difference in isotope ratios.

Excretion and Storage: How cancer cells handle the excretion and storage of copper might also contribute to changes in isotopic composition.

Metabolic Differences

Solid Tumors:

Hypoxic Environment

Solid tumors often grow rapidly and can outstrip their blood supply, leading to regions of hypoxia (low oxygen). Hypoxia induces the expression of hypoxia-inducible factors (HIFs) which activate genes that promote glycolysis. This results in solid tumors relying heavily on glycolysis to meet their energy needs.

Limited

OXPHOS

While some solid tumors may still utilize OXPHOS, especially in regions closer to blood vessels where oxygen is more available, the overall tendency is towards glycolysis due to the prevalent hypoxic conditions.

Project-29 investigates how solid tumors may behave differently than lymphoma

Lymphomas:

Oxygen Availability

Lymphomas generally have better oxygen availability as they often arise in lymph nodes and other organs with a well-maintained blood supply. This can support a higher reliance on OXPHOS compared to solid tumors.

Metabolic Flexibility

Lymphomas may exhibit more metabolic flexibility, switching between glycolysis and OXPHOS depending on the energy needs and the microenvironment. For instance, when lymphoma cells are in the bloodstream or in well-vascularized areas of lymph nodes, they might preferentially use OXPHOS.

OXPHOS in B-cell Lymphomas:

Research suggests that certain types of lymphoma, such as B-cell lymphomas, show a significant reliance on OXPHOS. This is possibly due to their origin from B cells, which naturally have high energetic and biosynthetic demands to produce antibodies.

Implications for
Treatment and Prevention

Targeted Therapies: Reprogramming of glucose metabolism is a very active field of research with therapies like GLUT inhibitors (eg, fasentin , STF-31, and WZB117), and drugs targeting Hexokinase (HK), Phosphofructokinase (PFK), Pyruvate Kinase (PK), Lactate Dehydrogenase (LDH), Aldolase (ALDO), Phosphoglycerate Kinase 1 (PGK1), Phosphoglycerate Mutase 1 (PGAM1), Enolase (ENO), Monocarboxylate Transporters (MCTs), and Isocitrate Dehydrogenase (IDH).

Lifestyle Changes: Addressing factors that can influence the metabolic processes of cancer includes, dietary (low carb), caloric restriction, physical activity, and healthy weight.