Uncategorized Thursday, 2024/08/29
We have previously reported various anti-cancer methods of a ketogenic diet.
For example, improving the sensitivity of drug-resistant cancer cells to anticancer drugs; Reducing PD-L1 levels, and enhancing the anti-cancer effect of CTLA-4 inhibitors; And the ketone body β – hydroxybutyrate produced by the ketogenic diet directly inhibits the formation and development of colon cancer, and so on.
Today, a research team led by Davide Ruggero from the University of California, San Francisco published a groundbreaking study in the top journal Nature.
They found that the ketogenic diet could not help pancreatic cancer. When switching from a normal diet to a ketogenic diet, pancreatic cancer continued to grow and was completely unaffected. However, they noticed that pancreatic cancer also paid a price to adapt to dietary changes: it switched its metabolic mode to the mode where ketone bodies can be used as energy through translation regulation.
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This change in pancreatic cancer suddenly made Ruggero’s team see the flaw: when taking a ketogenic diet, blocking the translation regulation pathway of pancreatic cancer with drugs can kill pancreatic cancer.
In a word, the research plan of Ruggero’s team at the beginning was not about ketogenic diet and pancreatic cancer, but about how fasting can change the metabolic mode and thus be beneficial to health.
After fasting the mice for 24 hours, they found that the phosphorylation level of serine at position 209 of eukaryotic translation initiation factor 4E (eIF4E) increased, and this phosphorylated eIF4E (P-eIF4E) was in an activated state. Moreover, the only known kinase of eIF4E, MNK, also increases its activity during fasting.
However, after the mice started eating, the level of P-eIF4E decreased. Obviously, the activity of eIF4E is influenced by feeding status.
At the transcriptome level, the translation efficiency of 615 transcripts was significantly up-regulated during fasting.
These genes are mainly involved in lipid metabolism, with ketone body production being the most important. For example, the rate-limiting enzyme Hmgcs2 for ketone body formation and the main regulatory factor PPARα for liver lipid metabolism/ketone body formation.
The transition from eating to fasting has altered the protein translation pattern of the liver, particularly increasing the translation of genes involved in lipid metabolism and ketone body production.
So are the above gene translation changes regulated by fasting induced P-eIF4E?
The answer is affirmative.
After site-directed mutation of eIF4E serine 209 (eIF4ES209A), compared with wild-type mice, mutant mice fasted for 24 hours produced significantly reduced levels of beta-hydroxybutyrate (BHB), the most abundant ketone body in the blood.
Moreover, among the 615 genes that were up-regulated during fasting, 445 genes were significantly down-regulated in the liver of mutant mice, including Ppara and Hmgcs2.
Subsequent studies have also confirmed that P-eIF4E directly interacts with specific regions of mRNA, thereby regulating protein translation.
In the above study, we have learned that fasting activates the MNK eIF4E pathway, leading to the activation of eIF4E phosphorylation, which in turn alters the translation network and promotes the production of ketone bodies.
So, the next question is: how does fasting activate the MNK-eIF4E pathway?
The Ruggero team noticed that previous studies have confirmed that one of the main characteristics of fasting is an increase in the levels of free fatty acids (such as palmitic acid, oleic acid, and linoleic acid) in the blood, and these fatty acids can also act as signaling molecules.
So, fatty acids became their breakthrough point.
After treating liver cells with the three types of fatty acids mentioned above, they found that these fatty acids could activate the MNK-eIF4E pathway, especially linoleic acid. However, these fatty acids do not directly act on MNK, but rather interact with AMPK upstream of MNK and activate AMPK, which in turn activates the MNK-eIF4E pathway.
Simply put, fasting increases levels of fatty acids. Free fatty acids interact with AMPK and activate AMPK, which then phosphorylates MNK. The phosphorylated MNK then phosphorylates eIF4E, promoting the formation of P-eIF4E and ultimately regulating the protein translation network to enhance ketone body levels.
Considering that a ketogenic diet also increases the production of ketone bodies, the Ruggero team wants to know if there is a similar mechanism behind it.
They found that after switching the diet of mice to a ketogenic diet, the phosphorylation level and activity of AMPK in the liver increased, and the level of P-eIF4E also significantly increased. Inhibiting AMPK activity with drugs will reduce the phosphorylation levels of MNK and eIF4E.
It is not difficult to see that P-eIF4E also regulates the production of ketone bodies in ketogenic diets.
At this point, a new anti-cancer idea emerged in the minds of Ruggero and his colleagues: some cancer cells also use ketone bodies as an energy source for survival. If the pathway discovered above is blocked, can it be anti-cancer?
They first tested the hypothesis with two pancreatic cancer cell lines.
The research results show that neither the ketogenic diet nor MNK inhibitor (eFT508) alone can inhibit tumor growth; the combination of a ketogenic diet and MNK inhibitors can significantly inhibit tumor growth.
The underlying reason is that the ketogenic diet reshapes the translation group of cancer cells. For example, the MNK-eIF4E pathway is activated in cancer cells, producing ketone bodies. In cases of energy deficiency, cancer cells use ketone bodies for energy supply.
The MNK inhibitor (eFT508) precisely blocks this process, leaving cancer cells with no “food” to eat under a ketogenic diet.
Overall, the study by Davide Ruggero’s team suggests that under fasting/ketogenic diet conditions, free fatty acids activate the AMPK-MNK-eIF4E pathway, thereby regulating the translation levels of specific genes in cells and reshaping their energy metabolism. It is reported that this is also the first time that scientists have discovered that P-eIF4E is involved in translation regulation.
For pancreatic cancer, under the condition of the ketogenic diet, cancer cells will reset their metabolic pathways through translation regulation to adapt to the problem of insufficient energy supply caused by the ketogenic diet. This not only reveals the mechanism of the ineffectiveness of the ketogenic diet on pancreatic cancer, but also provides a new idea for ketogenic diet combined with drugs to treat pancreatic cancer.
It is understood that the MNK inhibitor (eFT508) is already in the clinical research stage. It is worth noting that in addition to anti-cancer effects, a 2021 study by the Ruggero team also showed that eFT508 has the potential to treat obesity.
Looking forward to the follow-up research results of the Ruggero team.
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Reference
Yang, H., Zingaro, V.A., Lincoff, J. et al. Remodelling of the translatome controls diet and its impact on tumorigenesis. Nature. 2024. doi:10.1038/s41586-024-07781-7
Dmitrieva-Posocco O, Wong AC, Lundgren P, et al. β-Hydroxybutyrate suppresses colorectal cancer. Nature. 2022;605(7908):160-165. doi:10.1038/s41586-022-04649-6
Conn CS, Yang H, Tom HJ, et al. The major cap-binding protein eIF4E regulates lipid homeostasis and diet-induced obesity. Nat Metab. 2021;3(2):244-257. doi:10.1038/s42255-021-00349-z