Theme 1: Molecular regulation

Question 1

What is the difference between a tumour and cancer?

Answer 1

A tumour is a neoplasm that can be benign, pre-malignant, or malignant. Cancer is a malignant neoplasm characterized by uncontrolled growth, invasion, and metastasis.

Question 2

What are key features of cancer cells?

Answer 2

• Uncontrolled proliferation
• Invasion and metastasis
• Altered energy metabolism (Warburg effect)
• Resistance to apoptosis
• Genetic instability
• Deregulated cellular energetics.

Question 3

What are the eight hallmarks of cancer according to Hanahan and Weinberg?

Answer 3

1. Sustaining proliferative signalling
2. Evading growth suppressors
3. Resisting cell death
4. Enabling replicative immortality
5. Inducing angiogenesis
6. Activating invasion and metastasis
7. Evading immune destruction
8. Reprogramming energy metabolism

Question 4

What is the role of telomerase in cancer?

Answer 4

Telomerase prevents telomere shortening, allowing cancer cells to avoid cellular senescence and maintain replicative immortality.

Question 5

How do cancer cells generate energy differently from normal cells?

Answer 5

Cancer cells rely on glycolysis (Warburg effect), even in oxygen-rich conditions, producing ATP less efficiently but supporting biosynthesis.

Question 6

What are the key metabolic pathways altered in cancer cells?

Answer 6

Glycolysis, pentose phosphate pathway (PPP), glutaminolysis, fatty acid synthesis, and altered mitochondrial oxidative phosphorylation (OXPHOS).

Question 7

How does the TCA cycle contribute to biosynthesis in cancer cells?

Answer 7

The TCA cycle provides precursors for amino acid, lipid, and nucleotide biosynthesis through anaplerotic reactions.

Question 8

What are key mitochondrial functions in cancer cells?

Answer 8

• ATP production
• Metabolic substrate regulation
• Calcium homeostasis
• Apoptosis regulation
• ROS production
• Biosynthesis of macromolecules.

Question 9

How do mitochondria contribute to apoptosis?

Answer 9

Release of cytochrome c from mitochondria activates caspases, triggering apoptosis. Cancer cells suppress this process to evade cell death.

Question 10

What is the Warburg effect?

Answer 10

Cancer cells preferentially use glycolysis for ATP production even in the presence of oxygen, leading to increased glucose uptake and lactate production.

Question 11

How does the pentose phosphate pathway (PPP) support cancer metabolism?

Answer 11

The PPP generates NADPH for antioxidant defence and biosynthesis, while ribose-5-phosphate supports nucleotide production.

Question 12

How does lactate contribute to cancer progression?

Answer 12

Lactate lowers pH, suppresses immune response, and can be used as a carbon source for neighbouring tumour cells.

Question 13

What is glutaminolysis and its role in cancer?

Answer 13

Glutaminolysis replenishes the TCA cycle (anaplerosis) and provides precursors for biosynthesis.

Question 14

What are the sources of ROS in cancer cells?

Answer 14

ROS are generated from electron leakage at Complex I and III in the electron transport chain (ETC) and from NADPH oxidases.

Question 15

How do cancer cells regulate ROS levels?

Answer 15

Cancer cells upregulate antioxidant defences such as superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) to prevent oxidative stress-induced apoptosis.

Question 16

How does metformin inhibit Complex I and activate AMPK?

Answer 16

Metformin inhibits Complex I in the oxidative phosphorylation, leading to decreased ATP production and increased AMP:ATP and ADP:ARP ratio, which activates AMPK.

Question 17

What physiological intervention also activates AMPK?

Answer 17

Exercise and caloric or nutrient restriction activate AMPK by depleting cellular energy stores.

Question 18

How does AMPK regulate mTORC1?

Answer 18

AMPK inhibits mTORC1 via phosphorylation of TSC and raptor, which activates the TSC complex and inhibits Rheb, a direct activator of mTORC1.

Question 19

How do cancer cells evade apoptosis?

Answer 19

By upregulating anti-apoptotic proteins (BCL-2, BCL-XL), downregulating pro-apoptotic proteins (BAX, BID, BAK), suppressing caspases, and avoiding death receptor signalling.

Question 20

What are inhibitors of apoptosis proteins (IAPs)?

Answer 20

IAPs are a family of anti-apoptotic proteins that suppress caspase activity, preventing programmed cell death.

Question 21

What is autophagy’s role in cancer?

Answer 21

Autophagy helps cancer cells survive under metabolic stress by recycling cellular components for nutrient supply. Excessive autophagy can lead to cell death.

Question 22

How do lysosomes contribute to cancer cell survival?

Answer 22

Lysosomes degrade macromolecules and damaged organelles, supporting metabolic adaptation in tumours.

Question 23

How is the intrinsic apoptotic pathway activated?

Answer 23

It is activated by intracellular stress above a certain threshold signals such as radiation-induced stress, free-radical-induced stress and viral infections.

Question 24

What are the mitochondrial changes in the intrinsic apoptotic pathway?

Answer 24

Mitochondria are permeabilized, by BAX/BID or PTP opening, which results in
the loss of membrane potential, loss of bioenergetics and release of the pro-
apoptotic factors, such as cytochrome c and diablo.

Question 25

Which proteins are released from mitochondria during apoptosis?

Answer 25

Release of apoptosis-inducing factor (AIF) and endonuclease G (Endo G) and translocation to the nucleus promotes DNA fragmentation.

Question 26

How do these proteins activate caspases?

Answer 26

Cytochrome c binds to Apaf-1, forming the apoptosome, which activates caspase-9. Smac/DIABLO inhibits IAPs, promoting caspase activation.

Question 27

Why is PKM2 preferred by cancer cells over PKM1?

Answer 27

PKM2 has low activity and can be regulated, whereas PKM1 is constitutively on. Cancer cells need low PKM2 activity, because it allows for the build-up of upstream glycolytic intermediates that can be used in biosynthesis of essential cell components needed for cell growth.

Question 28

How is PKM2 regulated in cancer?

Answer 28

PKM2 is regulated by fructose 1,6-biphosphate, which induces the tetramerization of the PKM2 complex. AKT is able to inhibit the activity of the PKM2 tetramer.

Question 29

How does the TSC complex regulate mTORC1 activity?

Answer 29

The TSC complex inhibits the Rheb protein by activation of the GTPase activity of Rheb. In this way, Rheb transforms to the GDP bound state which is inactive and unable to activate mTORC1. The TSC complex can be phosporylated by AKT which which makes TSC inactive, away from Rheb and thus Rheb is activated which then can activate mTORC1.

Question 30

Why does rapamycin have limited clinical efficacy in cancer?

Answer 30

* Negative feedback mechanisms in the cell activate other growth signalling pathways like the MAPK pathway * Inactivation of mTOR by metformin can activate protein uptake from outside the cell (macropinocytosis) * Rapamycin can be more cytostatic than cytotoxic

Question 31

What strategies can improve rapamycin’s clinical efficacy?

Answer 31

Combining rapamycin with therapies that block growth pathways (e.g. PI3K inhibitors, AKT inhibitors) upon metformin treatment, or therapies that block autophagy pathways needed for macropinocytosis.

Question 32

What are the key metabolic alterations in cancer cells?

Answer 32

Increased glycolytic flux, altered TCA cycle, enhanced fatty acid synthesis, and accumulation of oncometabolites like succinate, fumarate, and 2-hydroxyglutarate (2-HG).

Question 33

Why do cancer cells undergo metabolic reprogramming?

Answer 33

To meet the biosynthetic and energetic demands of rapid proliferation while maintaining redox balance and avoiding apoptosis.

Question 34

What are the key metabolic regulators in cancer?

Answer 34

* PI3K/Akt/mTOR (promotes glycolysis and biosynthesis) * HIF-1α (drives glycolysis under hypoxia) * MYC (enhances glutaminolysis) * AMPK (regulates energy stress) * LKB1 (tumour suppressor controlling energy homeostasis).

Question 35

How does MYC contribute to cancer metabolism?

Answer 35

MYC upregulates glucose and glutamine metabolism, promoting nucleotide biosynthesis and cell proliferation.

Question 36

What is the function of AMPK in cancer?

Answer 36

AMPK acts as an energy sensor, activating catabolic pathways to restore ATP levels, but can also be hijacked by cancer cells for metabolic adaptation.

Question 37

What metabolic pathways are targeted in cancer therapy?

Answer 37

* Glycolysis (hexokinase inhibitors) * Glutaminolysis (glutaminase inhibitors) * FAO (CPT1 inhibitors) * Mitochondrial function (OXPHOS inhibitors).

Question 38

What is the role of immune checkpoint inhibitors in cancer metabolism?

Answer 38

Blocking PD-L1 or CTLA-4 can restore immune function and shift tumour metabolism toward a less proliferative state.

Question 39

How does hypoxia regulate cancer metabolism?

Answer 39

Hypoxia stabilizes HIF-1α, which upregulates glycolytic genes and promotes angiogenesis.

Question 40

How does the tumour microenvironment influence cancer metabolism?

Answer 40

The microenvironment supplies nutrients, oxygen, and growth factors while modulating immune response and metabolic competition with immune cells.

Question 41

Why do cancer cells rely on glutaminolysis?

Answer 41

Glutamine provides anaplerotic intermediates for the TCA cycle, supporting biosynthesis and redox balance.

Question 42

How does fatty acid oxidation (FAO) support cancer cell survival?

Answer 42

FAO generates ATP and NADPH, helping cancer cells survive metabolic stress and oxidative stress.

Question 43

What is the role of MYC in metabolic reprogramming?

Answer 43

MYC enhances glycolysis, glutaminolysis, and nucleotide biosynthesis, supporting rapid proliferation.

Question 44

How do oncometabolites drive cancer progression?

Answer 44

Oncometabolites like 2-hydroxyglutarate (2-HG), fumarate, and succinate inhibit α-KG-dependent enzymes, altering epigenetics and metabolism.