Cancer, Warburg and Fatty Acid Oxidation: A Clearer Understanding

The recent two-part series on fatty acid oxidation in cancer generated considerable confusion and many questions. Dr. Thomas Seyfried reached out to me specifically to help clarify this issue. The observation that some cancer cells can use fatty acids to support oxidative phosphorylation does not change the fundamental fact that these cells remain heavily dependent on glucose and glutamine for ATP production. Consequently, the dietary strategies we have discussed—particularly the ketogenic diet—as well as anti-Warburg metabolic therapies, continue to be highly relevant and important in these cancers.

There are no studies to our knowledge showing that fatty acids can replace glucose or glutamine for ATP production through OxPhos. Studies suggesting that tumor cells use fatty acids for energy are always done in the presence of glucose and glutamine. Indeed, palmitic acid (16:0) stimulates glucose uptake and glycolysis in prostate cancer cells. (1) These findings could suggest to those unfamiliar with cancer energy metabolism that prostate cancer cells use fatty acids for energy through OxPhos. We have reviewed extensive published evidence showing that cancer cells cannot use fatty acids for energy through OxPhos. (2) All major cancers store fatty acids in triglyceride lipid droplets in the cytoplasm.(3) This storage would protect the cancer cell from excessive ROS formation if oxygen were present in the environment. We have reviewed extensive published evidence showing that all major cancers have abnormalities in the number, structure, and function of mitochondria that would compromise the efficiency of OxPhos for maintaining growth. Can you explain how so many people are unable to understand or interpret these findings and continue to believe that some cancer cells have normal OxPhos and can use fatty acids for ATP production in the absence of glucose and glutamine?

Professor Thomas Seyfried.

The other side of the argument

Tumors May Use Both Glycolysis and OXPHOS

Many cancers generate ATP from:

• glycolysis,

• oxidative phosphorylation,

• fatty acid oxidation (FAO),

• glutamine metabolism,

often simultaneously.

Rather than being locked into one pathway, cancer cells are:

metabolically flexible.

However, the point emphasized by Professor Seyfried, is that cancer cells cannot generate ATP by oxidative phosphorylation alone and always require both glucose and glutamine.

PS: I would like to thank Prof. Seyfried for his invaluable input and insight; he is widely regarded as the leading authority on cancer metabolism.

References

1. Andersen KF, Divilov V, Sevak K, Koziorowski J, Lewis JS, Pillarsetty N. Influence of free fatty acids on glucose uptake in prostate cancer cells. Nucl Med Biol. 2014;41(3):254–8.

2. Seyfried TN, Arismendi-Morillo G, Mukherjee P, Chinopoulos C. On the Origin of ATP Synthesis in Cancer. iScience. 2020;23(11):101761.

3. Seyfried TN, Ta NL, Duraj T, Lee DC, Kiebish MA, Chinopoulos C, et al. Could cytoplasmic lipid droplets be linked to inefficient oxidative phosphorylation in cancer? Current Tissue Microenvironment Reports. 2024.