efecto warburg

Question 1

paradox ?

in Aerobic glycolysis: increased production of lactate from glucose and reduced beta oxidation

Answer 1

high-energy requiring cancer cells use low energy-yielding pathway.

Question 2

cancer cells are glycolytic in an abundance of oxygen… what does this mean?

Answer 2

they’ve been inherently altered in a way that favors glycolytic metabolism even in the presence of oxygen

Question 3

2 theories that might explain why cancer cells favor glycolytic metabolism ?

Answer 3

cell proliferation priortized since glycolysis provides most building blocks required for cell proliferatoin

to shut down the mitochondria involved in cell apoptosis program which would otherwise kill cancerous cells

Question 4

changes in cancer cells that support increased glycolysis ?

Answer 4

GLUCOSE TRANSPORTERS

*Over-expression of GLUT-1 in cancerous cells > anti-sense GLUT-1 studies suppressed cancer cell growth in vitro and tumor growth in vivo > highly efficient GLUT 3 also expressed and GLUT-12 upregulated in breast cancer > SGLT that drives glucose against concentration gradient upregulated in some cancer cells as well

*growth hormone receptor> AKT activated (a serine/threonine protein kinase) > phosphorylates HK-II which moves from cytosol to mt membrane > binds VDAK , allowing ATP out of the mitochondria to the cytosol > VDAK region will have the highest ATP concentration > HK-II phosphorylates glucose using such a high concentration of ATP > when ATP-bound, HK-II is unihibited by G-6-P > plus: VDAK binding stabilizes mitochondria and protects against apoptosis > this glycolytic mechanism is actually utilized by muscle and adipose tissue under insulin regulation > utilized by cancer cells in order to make glycolytic metabolism more efficient

*cancer cells have hyperactive PDK kinase, which inactivates PDH, and diverts pyruvate reserves into lactate

*cancer cells express fetal isoform of pyruvate kinase called PK-M2 (as opposed to adult cells that express PK-M1) > pyruvate product of M-2 is preferntially metabolized to lactate (makes sense as fetal metabolism should be more anabolic)

*replacing fetal PK-M2 in cancer cells with adult PK-M1 actually inhibits tumorgenesis

Question 5

cancer cells expand biomass at expense of efficiency of energy yield ? molecular explanation ?

Answer 5

PPP provides NADPH for lipid biosynthesis

Question 6

pyruvate dehydrogenase kinase cas cancer target drug ?

Answer 6

DCA (dichloroacetate) inhibits PDK –> PDH no longer inhibited –> pyruvate rather converted into acetyl coA (enters TCA cycle) > prevents lactic acidosis