Tryptophan pull kills cancer

Tryptophan, one of the amino acids from which proteins are built, appears to be a weak spot in tumor cells. If they no longer get tryptophan, they continue to make proteins with an alternative building block: phenylalanine. And that makes it possible for the immune system to distinguish the tumor cells from normal body cells, and to eliminate them. The research, conducted under the leadership of molecular biologist Reuven Agami of the Antoni van Leeuwenhoek in Amsterdam, appeared on wednesday in Nature†

Tryptophan is a so-called essential amino acid, which means that this molecule cannot be made by the body itself. You have to get it through food, otherwise there will be a shortage, causing the production of proteins to stop.

“If there is a shortage of a certain amino acid, normal cells temporarily lower their protein production,” says Agami, “but tumor cells continue. At the expense of the quality of the protein. Almost all cancer cells increase their protein production in order to grow. They don’t have much control over that process, so a shortage of the right building blocks doesn’t slow them down.”

If there is a shortage of tryptophan in the tumor cell, the enzyme that ensures that the correct amino acids are incorporated takes phenylalanine as an alternative. This enzyme does not neatly follow the order from the codon, the three-letter code for amino acids that is fixed in the DNA. Phenylalanine acts as a stand-in for tryptophan, allowing protein production to continue.

In 90 percent of the cases it is not that harmful, tryptophan and phenylalanine are somewhat similar. In terms of structure and therefore also usually in terms of function of the protein, they are only slightly different. Some proteins will undoubtedly lose their activity as a result of this change, but apparently the consequences are limited. Apparently phenylalanine is still a reasonably good spare part for the cancer cell.”

A new word

According to Agami, this is the first time that a human protein has been shown to change without being preceded by a mutation in the genetic code of the DNA. That justified using a new word Agami’s team came up with to describe the phenomenon: “substitutant” — a contraction of replacement and change at the same time at the protein level. “They had to go there” Nature think about it for a moment”, says Agami with a laugh. “They did a thorough investigation to see if this term wasn’t already being used for something else, but in the end they accepted it.”

The researchers expect that their discovery could lead to a new immunotherapy against cancer, which can also target tumors that are difficult to treat with existing immunotherapy (those with few mutations in their DNA). Tryptophan also plays an important role in how cancer cells protect themselves against attacks by T cells. These white blood cells recognize cells that do not belong in the body and can then eliminate them. Agami: “When a T-cell recognizes a cancer cell, a chain reaction starts inside the cancer cell to slow down the T cells. In doing so, that cell uses up all the tryptophan completely. That’s how melanomas do, for example. This allows tumor cells to escape the attack of the immune system. But because they use so much tryptophan for this, they actually have nothing left for making their proteins.”

protein pieces

This only increases the chance that cancer cells will use phenylalanine instead of tryptophan. Agami and his team searched international databases containing information about the composition of proteins in a variety of tumors and adjacent healthy tissue. Indeed, they found that tumor cells significantly frequently possessed tryptophan-to-phenyl-alanine substituents.

That’s good news, because it also means that these abnormal proteins could be detected by the immune system. All cells in the body display pieces of their internal proteins on their surfaces, small pieces about ten amino acids long, for the immune system to judge.

These protein pieces are presented by special receptors on the outside of the cell, so-called human leukocyte antigens (HLA). They differ from person to person. Depending on the type of HLA that someone has inherited, different pieces of protein are shown on the outside of the cell.

Experiments showed that tumor cells cultured under conditions in which tryptophan deficiencies develop in the cells did indeed present T cells recognizable pieces of protein with the substituent. In the blood of healthy individuals, the team was also able to isolate T cells that could recognize the strange piece of protein. “We see ten to thirty times higher activity against the mutant,” says Agami. “Proof for us that this mechanism can work for a new kind of cancer therapy.”

depression

A simple method is obvious: a diet from which tryptophan has been extracted. At the moment, Agami is already doing tests with mice to see if this works. Behavioral change is a side effect that the researchers expect. Tryptophan is an important building block of the messenger substance serotonin in the brain. If you remove it from the diet, there is a shortage of serotonin, which can cause depression. “We also saw that in the mice,” says Agami, “They lose their weight and can become aggressive. But if combining a tryptophan-free diet for a few days with a specific immunotherapy against substitutents proves to help against cancer, this could be a valuable treatment.”