"Cell Metabolism": Creatine actually promotes cancer metastasis!

When it comes to creatine, friends who love fitness are no strangers.

From the title of the article, everyone must have already seen that today we are bringing bad news about creatine.

Recently, a research team led by Bu Pengcheng from the Institute of Biophysics of the Chinese Academy of Sciences, Chen Gang from the Seventh Medical Center of the Chinese People’s Liberation Army General Hospital, and Park Hailong from the Institute of Chemical Physics of the Chinese Academy of Sciences published an important research result in the well-known journal "Cell Metabolism" .

They found that additional creatine supplementation, or excessive endogenous synthetic creatine, would aggravate the metastasis of colorectal cancer and breast cancer in mice.

Among them, the Smad2/3 pathway is the key to regulating cancer metastasis.

Therefore, the article points out that creatine synthesis, or Smad2/3 pathway, may become a new target for inhibiting cancer metastasis [1].

▲ Screenshot of the homepage of the paper.
We all know that colorectal cancer is the third most deadly cancer.
If it is accompanied by liver metastasis, even after treatment, the five-year survival rate of patients is only 10%.

At present, due to the unclear metastasis mechanism, the effect of the treatment of colorectal cancer is very unsatisfactory.

Creatine is a nutritional supplement that is often used by healthy people to strengthen muscle mass and function.

You may be curious, how can creatine be linked to bowel cancer? This is because cancer patients are prone to continuous decline of skeletal muscle mass and abnormal metabolism of cachexia.
Studies have shown that supplementing creatine through diet can repair patients' cachexia caused by colorectal cancer [2].

In other words, creatine supplementation may be beneficial for patients with bowel cancer.

However, due to insufficient and consistent studies to prove the effect of creatine supplementation on cancer patients, there is no clear clinical recommendation for cancer patients to take creatine [3].

Therefore, in order to explore the effect of creatine on the cancer itself, the researchers induced cancer by injecting colorectal cancer cells into mice, and added creatine in the diet of the experimental group of mice in proportion to the human intake.

They found that the primary tumor of the cecum in the mice that ate creatine became smaller.

This seems to be a good sign.

However, both visual observation and luciferase tracking showed that mice that ate creatine had more serious colorectal liver metastases.

In order to verify whether this phenomenon is limited to colorectal cancer, the researchers constructed an additional batch of breast cancer mice and performed the same experiment.

The results showed that after the mice took creatine, the size of primary breast tumors decreased, but the number of lung metastases increased.

Therefore, too high creatine can cause aggravation of metastases.

▲ Creatine can exacerbate liver metastasis from bowel cancer (ND: normal diet; Cr: creatine).
At the same time, they also found that the creatine content in the primary tumor and metastases were significantly increased.

In addition, after injection of tumor cells in which creatine transferase (SLC6A8) was knocked out, the mice that ate creatine did not develop more serious metastases.

This indicates that creatine accumulated in cells is an important factor in promoting metastasis.

Unexpectedly, creatine will promote cancer metastasis! You know, creatine can not only be obtained from food, but we animals can also synthesize creatine by ourselves.

So will the self-synthesized creatine promote the metastasis of cancer? In the human body, the synthesis of creatine is mainly regulated by glycine amidinotransferase (GATM), etc.
Moreover, GATM is also an important rate-limiting enzyme in the process of creatine synthesis.

So is there any relationship between creatine synthesis and cancer metastasis? They found that the expression of GATM was significantly increased in the colorectal and liver metastases of mice and patients compared with the primary tumors.

In order to further verify whether GATM can regulate the metastasis of colorectal cancer, the researchers found that the migration ability of cancer cells was significantly improved after ectopic expression of GATM in the cells.

In a mouse model injected with GATM overexpressing cancer cells, colorectal liver metastasis was significantly increased.

At the same time, in mice injected with GATM knockout cells, the extent of liver metastasis and the size of metastases were inhibited.

▲ GATM overexpression promotes liver metastasis of colorectal cancer (EV: blank vector; GATM: GATM overexpression) Since GATM may regulate colorectal metastasis, what downstream pathways will be involved? In cancer cells with high GATM expression, the researchers found that the phosphorylation of Smad2/3 increased.

Generally speaking, Smad2/3 is downstream of Tgfbr1 and is activated by phosphorylation.

However, studies have shown that the phosphorylation of Smad2/3 caused by creatine is not changed in the case of Tgfbr1 mutation.

Therefore, the researchers concluded that the phosphorylation of Smad2/3 caused by creatine is a pathway independent of Tgfbr1.

Among them, MPS1 has been reported to cause Smad2/3 phosphorylation independent of the Tgfbr1 pathway [4].

To determine whether creatine phosphorylates Smad2/3 through MPS1, they knocked out MPS1 in cancer cell lines.

In such cells, they observed that the degree of creatine phosphorylation of Smad2/3 was significantly reduced.

In MPS1 mutant mice, colorectal liver metastasis caused by creatine was significantly suppressed.

At the same time, the aggressiveness of the primary tumor and the phosphorylation of Smad2/3 were suppressed.

Finally, in order to verify whether MPS1 has the potential as a chemotherapy target, the researchers injected the MPS1 inhibitor MPS1-IN-3 through the intraperitoneal cavity.

It was found that the drug prolonged the survival period of mice with colorectal cancer, reduced the invasiveness of the primary tumor, and inhibited liver metastasis.

▲ Mechanism diagram Generally speaking, in mice with colorectal cancer and breast cancer, excessive creatine supplementation will reduce the size of the primary foci to a certain extent, but it will significantly aggravate the metastasis of cancer cells.

In this view, cancer patients may not be suitable for additional creatine supplementation.

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 References: 1.
Zhang L, Zhu Z, Yan H, et al.
Creatine promotes cancer metastasis through activation of Smad2/3 [published online ahead of print, 2021 Mar 27].
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2021;S1550-4131(21) 00116-9.
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Di Biase S, Ma X, Wang X, et al.
Creatine uptake regulates CD8 T cell antitumor immunity.
J Exp Med.
2019;216(12):2869 -2882.
doi:10.
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Jatoi A, Steen PD, Atherton PJ, et al.
A double-blind, placebo-controlled randomized trial of creatine for the cancer anorexia/weight loss syndrome (N02C4): an Alliance trial .
Ann Oncol.
2017;28(8):1957-1963.
doi:10.
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Hoover LL, Kubalak SW.
Holding their own: the noncanonical roles of Smad proteins.
Sci Signal.
2008;1(46): pe48.
Published 2008 Nov 18.
doi:10.
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146pe48 Author of this articleResponsible editor of CindyBioTalker