Fasting and ketogenic diet reveal new vulnerability of pancreatic tumors to existing cancer drug

By Dr. Liji Thomas, MDReviewed by Benedette Cuffari, M.Sc.Aug 21 2024

In a recent study published in Nature, researchers examine the role of fasting and ketogenesis in regulating protein synthesis and its potential implications for cancer therapy.

Study: Remodelling of the translatome controls diet and its impact on tumorigenesis. Image Credit: Vink Fan / Shuttersotck.com

Health benefits of fasting

Fasting has been historically recommended for its health benefits, with records dating back to ancient Greece.

The health benefits associated with fasting can be attributed to ‘metabolic rewiring,’ during which the body utilizes ketone bodies for energy instead of glucose. This stimulates weight loss, reduces inflammation, improves brain function, and may protect against cancer. Fasting may also support gut health by promoting a healthier and more diverse microbiome, support the regulation of key hormones including human growth hormone (HGH), leptin, and ghrelin, as well as increase longevity through its anti-aging effects.

Fasting, a high-fat low-carbohydrate diet, and exercise can induce ketogenesis, which is involved in various cellular signaling pathways. Despite extensive research on the biological mechanisms that may be responsible for the health benefits of fasting, it remains unclear how this dietary approach alters the proteome.

Effects of fasting on protein translation

During fasting, fatty acid levels rise due to the breakdown of fats, thereby providing an alternative source for energy production.

Fasting also inhibits the mammalian target of rapamycin (mTOR) pathway, which is a kinase that is traditionally involved in the synthesis and translation of proteins. The reduced activity of mTOR during fasting subsequently leads to reduced protein synthesis, particularly in the liver.

However, the synthesis of certain liver proteins increases during fasting, an effect that is mediated by phosphorylation of the eukaryotic translation initiation factor 4E (P-eIF4E). P-eIF4E plays a crucial role in regulating the translation of various proteins that are crucial for ketone production.

What is P-eIF4E?

Long-chain fatty acids produced during ketogenesis bind to adenosine monophosphate (AMP)-activated protein kinase (AMPK), which activates glucose and increases the uptake of fatty acids during low energy states. AMPK activity also activates mitogen-activated protein kinase (MAPK)-interacting protein kinase (MNK), which phosphorylates eIF4E; therefore, AMPK is key a regulator of ketogenesis through P-eIF4E.

This pathway, which is otherwise referred to as the AMPK-MNK-eIF4E axis, is a crucial aspect of selective protein translation that occurs during ketogenic states like fasting. Rising P-eIF4E levels during fasting leads to increased translation of specific messenger ribonucleic acids (mRNAs) involved in lipid catabolism and ketone body production. The binding of P-eIF4E to translation regulatory elements in the 5’ untranslated regions (5’ UTRs) upregulates these genes.

Cancer metabolism and the AMPK-MNK-eIF4E axis

Certain cancers, especially those that originate in the pancreas, can adapt to low-glucose environments by converting their energy source to ketone bodies. During this form of metabolism, cancerous cells may rely on P-eIF4E for their growth and metastasis.

In an effort to elucidate the role of ketogenesis in cancer cell survival and proliferation, the researchers of the current study explored the potential anticancer effects of the P-eIF4E inhibitor tomivosertib. To this end, tomivosertib treatment led to a significant reduction in P-eIF4E levels and ketogenesis in mice; however, no significant effects on body weight or blood glycerol and fatty acid levels were observed.

Thus, P-eIF4E inhibition leads to the reduced translation of mRNAs involved in ketogenesis, which subsequently prevents ketone production and affects the metabolism of lipids involved in cancer cell growth.

Conclusions

The current study demonstrates the crucial role of the AMPK-MNK-eIF4E axis in linking lipid metabolism with selective protein translation during fasting and ketogenesis. Through this pathway, P-eIF4E supports homeostasis within the liver by facilitating the production and release of ketone bodies as an alternative energy source when glucose is not available.

In the future, the researchers of the current study anticipate that combining a ketogenic diet with P-eIF4E inhibitor treatment has the potential to treat pancreatic cancer. Although the current study only examined the role of ketogenesis and P-eIF4E in the context of pancreatic cancer, additional research is needed to explore whether this type of translational regulation extends to other cancers and tissue types than liver cells.

Our findings unveil a new fatty acid-induced signalling pathway that activates selective translation, which underlies ketogenesis and provides a tailored diet intervention therapy for cancer.”