Recently, a research team led by Professor Carol Prives of Columbia University found a mevalonate pathway, a signal pathway controlled by the p53 gene. When the p53 gene is mutated and the function is lost, the mevalonate pathway will be out of control, which will increase the risk of liver cancer.

Scientists were also pleasantly surprised to find that statin, a widely used lipid-lowering star drug, targeted this mevalonic acid pathway and confirmed that lovastatin is indeed effective in treating cancer. The research results were published in the top international journal "Cell".

The reason why the p53 gene mutation is so close to cancer is because its function is so important.

In fact, the p53 gene is the patron saint of the human body. It has the functions of initiating cell cycle arrest, DNA repair, and apoptosis. These processes are important means of preventing cancer.

In addition, the p53 gene plays an important role in the regulation of aging, angiogenesis, autophagy, and metabolism, and these processes are also related to cancer.

And once this patron saint has an accident (mutation) and there is a lack of function, then the problem becomes bigger.

Because it is a loss-of-function mutation, there is no good way to make up for its lack.

Since the p53 mutation itself is not easy to start, scientists turned their attention to the downstream controlled by the p53 gene.

In 2012, a study published on Cell by Professor Carol Prives' team pointed out that in p53-mutated breast cancer cells, many genes related to the mevalonate pathway were up-regulated.

In 2016, a review on Nature Reviews Cancer summarized the relationship between the mevalonate pathway and tumors in detail, and pointed out that activation of this pathway may promote tumorigenesis.

Statin is a very effective lipid-lowering drug, it can inhibit HMG coenzyme A reductase, can effectively reduce cholesterol levels and reduce the risk of cardiovascular disease. (The discovery of statin drug targets has a legendary story)

The HMG CoA reductase is the rate-limiting enzyme of the mevalonate pathway, which means that statin targets the mevalonate pathway!

Moreover, there have been reports that taking statins is associated with a reduced risk of cancer deaths, including prostate cancer, kidney cancer, colorectal cancer, breast cancer, and lung cancer.

The junction of the p53 mutation and statin appears to be in the mevalonate pathway.

Professor Carol Prives' team continued to explore the relationship between p53 gene and mevalonate pathway and tumor.

Her team first demonstrated in cells and mice that the p53 gene can indeed inhibit the mevalonate pathway. Searching the tumor database also found that the mevalonate pathway is more active in tumor cells with p53 loss of function mutations.

In the liver, cholesterol produced by the mevalonate pathway accounts for 80% of human body cholesterol, and p53 mutations are very common in hepatocellular carcinoma.

This may imply that the p53 mutation is closely related to the mevalonate pathway and hepatocellular carcinoma.

Therefore, they constructed a mouse liver cancer model and confirmed that p53 can indeed inhibit the occurrence of liver cancer at an early stage. During the start of this cancer suppression program, the mevalonate pathway is strictly controlled by p53.

When p53 loses function, liver cancer is rapidly induced, and the mevalonate pathway is also significantly up-regulated.

Interestingly, in mice with p53 mutations, the mevalonate pathway is inhibited by other means, and the occurrence of liver cancer no longer occurs. Moreover, the treatment of mice with atorvastatin can also significantly limit the growth of tumors!

Lovastatin can effectively treat liver cancer

This indicates that the liver cancer caused by the p53 mutation is mediated by the mevalonate pathway, and that the mevalonate pathway de-suppression is necessary for the occurrence of liver cancer.

How does p53 inhibit the mevalonate pathway?

The researchers used qChip technology to identify a protein called SREBF-2 that would be affected by the p53 gene.

This SREBF-2 protein is the main regulator of the mevalonate pathway and does not normally have transcriptional activity. Only when the SREBF-2 protein senses the signal and becomes a mature protein will it be active and start the mevalonate pathway.

The way the p53 gene affects the SREBF-2 protein is to prevent it from maturing. However, scientists also found that P53 protein and SREBF-2 do not directly interact, requiring the hands of "others".

This "other" is the cholesterol transporter ABCA1. The p53 gene activates the expression of the ABCA1 gene, and the ABCA1 protein prevents the SREBP-2 protein from maturing, thereby inhibiting the mevalonate pathway.

They also searched the cancer database and found that in p53-mutated hepatocellular carcinoma, the expression level of the ABCA1 gene was lower than normal. This shows that ABCA1 gene may also be an important tumor suppressor gene.

When the ABCA1 gene of the mouse was knocked out, the mature SREBF-2 protein increased, and tumors developed more rapidly. This confirms that the anti-cancer function of ABCA1 gene is indeed exerted by inhibiting SREBF-2 protein.