Cancer

Question 1

LDH-A (cancer)

Answer 1

• M (muscle) LDH isoform, so it favors the anerboic pyruvate-> lactate, diverting cancer cell metabolism to glycolysis

Question 2

PDK (cancer)

Answer 2

• PDH-kinase
• inhibits PDH (pyruvate DH, which starts Kreb’s with pyruvate -> acetyl coA + CO2), thus diverting metabolism away from Kreb’s cycle

Question 3

HIF alpha and VHL (cancer)

Answer 3

• Hyopoxia-inducible factor alpha, a TF
• favors hypoxic CHO metabolism
• > via PDK, LDH-A
• normally levels are kept low by hydroxylation (O2 levels -> prolyl hydroxylase -> VHL -> ubiquitinated)
• cancer mutates VHL (tumor suppressor) -> active HIF

Question 4

PKM2 (cancer)

Answer 4

• slow isoform of Pyruvate kinase, which keeps glycolysis from exhausting growth metabolites needed by the cancer cell

Question 5

IDH (cancer)

Answer 5

• Isocitrate DH
• isocitrate -> alpha KG, a part of Kreb’s cycle
• 3 isoforms: 2 and 3 are mitochondrial (Kreb’s), 1 is cytosolic
• mutation of isoform 1 (IDH1) forms 2 hydroxy-glutarate (2HG), which
• inhibits the hydroxylation of HIF-alpha (see above)
• epigenetically modifies DNA mechanisms -> magic-> tumorogenesis

Question 6

Overview of cancer metabolism

Answer 6

Oncogenes -> expression -> high glycolysis
 - LDH-A
 - PDK
 - PKM2
Tumor suppressor gene
 - VHL normally suppresses HIF
Mutant:
 - IDH 1 -> 2HG (-> HIF, transformation)

PET scan measures high glucose uptake