- Muhammad Yaseen Nivas
All cells need oxygen to survive. Living cells. But maybe not cancer cells (some). Because some of them find ways to bypass oxidative metabolism.
Today’s scientific review article is about the Warburg Effect.
TLDR: It’s most efficient to use oxidative phosphorylation to extract energy out of a carbohydrate, but cancerous cells avoid it, even in the presence of abundant oxygen.
Now that the 10 second attention span folk have left, lets get to the juicy bits. Let’s discuss the normal way a cell would use glucose.
First it would break the glucose down into two 3-carbon sugars, generating some ATP on the way. Then it would run the 3-carbon sugar down the Kreb’s cycle, extracting some electrons and generating more ATP in the process. Finally, it runs the extracted electrons down an ‘electrogradient’ hill (with oxygen at the bottom, which is why oxygen is essential for survival, because it creates the hill), extracting energy at every step of the downhill movement. Sweet.
What cancerous cells do is to heavily rely on glycolysis, even though oxidative phosphorylation is 19 times better (net ATP yield in glycolysis is 2 and oxidative phosp. is roughly 38)! Upcoming radiologists should know that this phenomenon is used clinically to detect cancers (via FDG-PET).
So why does this occur? In short, there is no concrete answer but there are a few observations worthy of mention.
Tumors expand really fast. Sometimes, proliferation is so quick, the rate of angiogenesis around the tumor cannot catch up to supply the tumor well. This leads to hypoxia in the tumor, which then leads to the production of the Hypoxia-Induced Factor protein. Putting one and one together, it does become more advantageous for the cell to switch to glycolysis than wait for the vessels to be laid down.
Caption: Functions of HIF: Amongst other effects, HIF upregulates Pyruvate dehydrogenase kinase, which phosphorylates pyruvate dehydrogenase, which catalyzes the precursor step of oxidative phosphorylation so the net effect is a deregulation of the pyruvate->acetyl coA conversion. HIF also upregulates the lactate dehydrogenase enzyme, which is a key player in the lactic fermentation pathway.
Another observation is the fact that, disruptions in the proto-oncogenes observed in cancer actually favors glycolysis. For example, synthesis of the cyt c oxidase protein requires a normal p53 gene (a tumor suppressor gene which is dysfunctional in some cancers). Thus, a dysfunctional p53 in cancers would force cells to rely more on glycolysis than usual.
A good student of biochemistry will be aware of the isoform of pyruvate kinase, M2-PK, which is a cancer-specific isoform. From the discussion, one might expect it to be more efficient at the conversion of PEP to pyruvate than the normal protein, but lo! it turns out to be less efficient. This allows for the previous substrates of the glycolytic pathway to be shunted into biosynthetic pathways, which are crucial for the rapidly growing cancer cell. However, its a trade-off. The efficiency of energy production decreases, but you have more ‘building’ material.
Although a lot of research has been established regarding the warburg effect, much of what we’re dealing with is unknown land. This is a humbling reminder of how little we know about the universe, and it is fascinating, because we never know whether the next step might lead us into a breakthrough. Stay tuned for the next issue for another intriguing topic!
2. Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008 Sep 5;134(5):703-7. doi: 10.1016/j.cell.2008.08.021. PMID: 18775299.