Summary: 1.2: Metabolic Reprogramming | Jaap Keijer

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• 1 Metabolic Reprogramming

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• Why do cancer cells display aerobic glycolyis (4)?

  1: most abundant extracellular nutrient (glucose) is used to produce ATP
  2: glucose degradation provides intermediates needed for biosynthesis (growth)
  3: reduces ROS in low O2 levesls
  4: contributes to apoptosis resistance
  
  Systemic aerobic glycolysis would result in a waste problem (lactate)

• What is the original glycolysis pathway? What is the reprogrammaed glycolysis pathway?

  Original: glucose is converted into pyruvate, with the use of hexokinase. It yields 2 ATP and reduces NADH from NAD+. (NADH and) pyruvate enters the mitochondrium and the TCA cycle.
  Reprogrammed: pyruvate is converted into lactate by lactate-dehydrogenase (LDH-A), and oxidises NAD+ from NADH. Lactate is excreted.

• What is cataplerosis? What is anaplerosis? Which anaplerotic mechanism is most dominant?

  Cataplerosis: continuous efflux of intermediates in TCA cycle. Proliferating cells use the TCA cycle for biosynthesis: ATP is consumed rather than produced. 
  Anaplerosis: influx of TCA cycle intermediates. Used to resupply lost intermediates due to cataplerosis.
  The predominanat anaplerotic mechanism is glutaminolysis.

   

• 2 Regulation of Metabolic Activity

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• What is the major difference in regulation of metabolism between normals cells and cancer cells?

  In normal cells, regulation requires extracellular signalling. Without growth-factor signalling, they switch to autophagy.
  In cancer cells, regulation is autonomous and independent of growth factors. The same pathways are used, but the external signalling pathways are mutated: metabolic phenotype of biosynthesis independently of normal physiologic constrains. 

• How does p53 affect metabolism (3)? How does it react to (oxidative) stress?

  1: promotes OXPHOS, both in nucleus and mt. 
  2: downregulates expression of glucose transporters
  3: activates pentose phosphate pathway (PPP), provides NADPH for lipid and nucleotide synthesis, and forms antioxidant defence.
  Low stress: antioxidant, repair, survival -> tumor suppression.
  High stress: pro-oxidant, senescence, apoptosis in order to suppress tumors.

• What is LKB1, and how does it affect metabolism?

  It is a serine/threonine kinase 1. Via activation of AMPK, it inhibits mTOR, which will lead to repression of protein synthesis, cell growth and viability. AMPK inhibits biosynthesis and growth, and activates catabolism.

• What is mTOR? What is the difference between the two complexes mTORC1/2?

  mTOR is a signal integrator, regulates balance between cell survival and cell proliferation.
  mTORC1 is nutrient, energy and growth factor sensitive.
  mTORC2 is growth factor sensitive.

• What are the functions of mTORC1 and 2?

  mTORC2 acts upon SGK and Akt, regulating survival, proliferation and glucose uptake. Akt acts upon mTORC1.
  mTORC1 regulates translation, proliferation, survival; lipid biogenesis; angiogenesis (HIF-1a); inhibits autophagy. It's a signal integrator for four major regulatory inputs: nutrients, growth factor, energy and stress. 

• How are mTORC1 and 2 involved in tumorigenesis?

  mTORC1: indirectly upregulates fatty acid synthase (FAS), promotes lipid biogenesis; suppresses autophagy; promotes angiogenesis via HIF-1a.
  mTORC2: activates Akt, which promotes survival, proliferation and nutrient uptake in cancer cells.

• What is HIF, what is the difference between a/B?

  Hypoxia-inducing factor (HIF) is a heterodimeric transcription factor complex, consisting of one HIFa (1,2,3) and one HIF-1B. The HIFa subunits are regulated, HIFB is constitutively expressed.