Original Swagpp Metz Medical
Fatigue and anxiety? Difficulty falling asleep? lose weight? Dry hair? Have you suddenly experienced similar situations with unknown reasons? If there is! It is likely that the body is lacking some amino acid.
Amino acids are the basic building blocks of proteins and an important component of human tissues, playing a crucial role in the nutrition, survival, and development of living organisms. The role of amino acids covers multiple aspects. In addition to maintaining protein balance in the body, they also participate in the formation of hormones, enzymes, and antibodies, and maintain normal metabolism in the human body.
The amino acids that make up proteins in the human body are divided into two categories: 8 essential amino acids and 10 non essential amino acids. The former refers to the requirement of the human body that cannot be synthesized on its own and must be supplied by exogenous obligations, including isoleucine, leucine, phenylalanine, methionine, tryptophan, lysine, valine, and threonine.
Source: PSM Medicine Shield Public Welfare
Although the human body cannot do without amino acids, more is not necessarily better.
Recently, a joint research team from Sun Yat sen University and UPMC Sherman Cancer Center found that supplementing too much methionine in the diet may accelerate tumor growth and counteract the effectiveness of cancer treatment; On the contrary, limiting methionine in the diet can enhance anti-tumor efficacy! The study was published in the Nature Cancer sub journal.
doi: 10.1038/s43018-024-00748-7
As for the mechanism behind it, it all starts from the 'head'.
Glioblastoma (GBM) is the most common primary malignant brain tumor, with a median survival of less than 2 years. At the same time, the tumor has a high recurrence rate, often within 2-3cm of the original resection cavity, and grows in a nodular shape. In fact, there are many reasons why GBM patients cannot be cured, but one important one is the presence of glioblastoma stem cells (GSCs).
GSCs are a stem cell like population with strong resistance to radiotherapy and chemotherapy, and can produce cell type grading within tumors. Not only that, researchers have also confirmed through mouse and in vitro experiments that GSCs have a high translation rate, which means that the protein synthesis rate of GSCs is relatively high, and this high translation feature increases the invasiveness of GBM, making people "pale in comparison to glioblastoma".
GSCs have a high translation rate
Of course, the high translation rate of GSCs does not appear out of thin air. Researchers further used CRISPR gene knockout screening to explore potential tRNA modification factors that affect GSC growth and translation. After targeting 111 genes for screening, we finally found YRDC.
Specifically, researchers identified 9 important hit genes in GSC456 cell screening; And 12 types were found in GSC23 cell screening. Among them, only two genes, YRDC and RPUSD2, overlapped.
Based on this, the researchers concluded that YRDC is the most important tRNA modifier in GSCs. More precisely, YRDC is essential in most cancer cell lines.
So, how important is YRDC for GSCs?
After a series of analyses, researchers found that targeting YRDCs can reduce the survival rate of GSCs, consuming YRDCs can decrease the self-renewal ability of GSCs, and GSCs lacking YRDCs can also exhibit slower translation rates. It can be seen that YRDC plays an important role in maintaining GSC.
The process of screening YRDC
In fact, the root of the role of YRDC lies in catalyzing the biosynthesis of N6 threonine carbamoyl adenosine (t6A) on tRNA, thereby playing a role in regulating protein translation in GSCs.
Mass spectrometry analysis (MS) showed that targeting YRDC can reduce t6A, hinder protein translation, and inhibit tumor growth both in vivo and in vitro.
YRDC plays a crucial role in maintaining and translating GSCs
After much anticipation, Threonine has finally arrived - researchers have discovered that Threonine is an important substrate for YRDC.
A series of in vitro experiments have shown that threonine can dynamically regulate t6A levels. Specifically, when the concentration of methionine in the culture medium was increased, that is, after 72 hours of supplementing methionine, the concentration of t6A was increased, but it did not affect the total adenosine level.
Not only that, increasing the level of methionine can also accelerate translation. Compared with arginine, which is also an essential amino acid, supplementing with threonine can accelerate translation without affecting mTOR phosphorylation levels. In fact, threonine can promote translation through the biosynthesis of YRDC and t6A, thereby accelerating tumor growth.
Threonine dynamically regulates t6A and translation
Since the essential amino acid methionine needs to be supplemented through diet, can dietary intervention improve cancer therapy?
In order to better simulate the clinical application of methionine dietary restriction, researchers conducted dietary intervention and drug treatment 7 days after implantation of GSCs.
The results showed that after dietary restriction of methionine, the tumor volume in mice was significantly reduced, and the survival rate was also prolonged. More specifically, dietary restrictions on methionine reduce the biosynthesis of t6A, thereby inhibiting tumor protein synthesis and tumor cell cycle progression; A similar situation also occurred in xenograft experiments, where dietary restriction of methionine can effectively limit protein translation and proliferation of GSCs in vivo.
Looking at clinical practice, if the first-line chemotherapy drug temozolomide can be combined with dietary restrictions on methionine, there is great hope to enhance the anti-tumor efficacy of chemotherapy and anti mitotic therapy, providing a molecular basis for dietary intervention in cancer treatment.
Dietary restriction of methionine effectively enhances chemotherapy therapy
In summary, there is a close relationship between diet and health - by limiting the amount of methionine in the diet, it can effectively reduce the cell viability of GSCs, inhibit tumor growth, and prolong survival rates. For patients with glioblastoma, chemotherapy combined with dietary restriction of methionine may enhance anti-tumor efficacy and bring hope for survival!
Seeing this, I believe everyone's most concerned question is: Where does the methionine in the diet come from? Common natural foods include cheese, poultry, fish, meat, beans, kidney beans, sesame seeds, and so on. Under normal circumstances, adults require 20mg/kg of methionine per day.
Finally, this article does not encourage people to "limit their intake of methionine in their diet". As one of the essential amino acids, methionine also has many physiological functions, including lipid metabolism, protein synthesis, embryonic stem cell proliferation, alleviating anxiety and mild depression, etc. It is not necessary to kill it with one stick.
Appropriate and balanced is the way to success.
reference material:
[1]Wu X, Yuan H, Wu Q, Gao Y, Duan T, Yang K, Huang T, Wang S, Yuan F, Lee D, Taori S, Plute T, Heissel S, Alwaseem H, Isay-Del Viscio M, Molina H, Agnihotri S, Hsu DJ, Zhang N, Rich JN. Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming. Nat Cancer. 2024 Mar 22. doi: 10.1038/s43018-024-00748-7. Epub ahead of print. PMID: 38519786.
撰文 | Swagpp
编辑 | Swagpp
Original title: "Beware of this amino acid! Nature sub journal: Sun Yat sen University latest, eating too much of this' essential amino acid 'may accelerate tumor growth and inhibit anti-cancer efficacy
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