In brief

Branched-chain amino acids increase the risk and severity of liver cancer, according to A*STAR researchers.

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Starving liver cancer cells into submission

29 Jul 2019

Researchers reveal that the buildup of branched-chain amino acids fuels the growth and aggressiveness of liver cancer cells.

Proteins are an essential part of a healthy diet, but liver cancer cells have found a way to make use of certain amino acids from proteins to fuel their growth at the expense of the body. These findings were published by scientists from A*STAR’s Singapore Bioimaging Consortium (SBIC), National Cancer Centre Singapore, Duke Molecular Physiology Institute and the University of Rhode Island.

Branched-chain amino acids (BCAAs) like leucine, isoleucine and valine are essential amino acids that cannot be produced by the body and must be obtained from food. However, researchers have now found that cancer cells reprogram their metabolic networks to accumulate BCAAs, which can increase tumor cell growth by activating the protein mTORC1.

The team first compared the transcriptomes of tumor and non-tumor liver tissues in both humans and mice, identifying the loss of BCAA metabolism as a key difference between healthy and diseased tissue. The high levels of BCAAs in tumor cells were attributed to suppression of catabolic enzymes that under normal circumstances break down BCAAs.

To confirm the role of BCAAs in tumor formation, the researchers reduced the amount of BCAAs in the diet of mice with liver cancer and found a significant reduction in liver tumor size. Correspondingly, the extent of suppression of these catabolic enzymes in human tumor samples correlated with their aggressiveness, degree of metastasis, as well as the patient’s clinical outcome.

It is currently common practice to supplement the diet of liver cirrhotic patients with BCAAs to reduce the risk of developing hepatic encephalopathy, which is brain damage caused by the decline in liver function. However, these new findings may alter the way liver disease patients are treated.

“Now that we know chronic BCAA supplementation increases the risk and severity of liver cancer, especially in high-risk patient groups (i.e., liver diseases), we should evaluate patients’ BCAA catabolic efficiency before administering BCAAs for long-term treatment,” said Weiping Han at SBIC, team leader of the study. “We are also planning dietary interventions in patients with advanced liver diseases.”

With the identification of BCAA metabolism as a new target for liver cancer prevention and therapy, the team now intends to explore the applicability of these findings in gastrointestinal malignancies such as colorectal and gastric cancers.

The A*STAR-affiliated researchers contributing to this research are from the Singapore Bioimaging Consortium (SBIC).

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Ericksen, R. E., Lim, S. L., McDonnell, E., Shuen, W. H., Vadiveloo, M., et al. Loss of BCAA Catabolism during Carcinogenesis Enhances mTORC1 Activity and Promotes Tumor Development and Progression. Cell Metabolism 29, 1151-1165 (2019) | article

About the Researcher

Weiping Han obtained his PhD degree from Cornell University and did postdoctoral work at the University of Pittsburgh and HHMI/UT Southwestern Medical Center. In 2005, he moved to Singapore to set up a research program in the Laboratory of Metabolic Medicine (LMM) at the Singapore Bioimaging Consortium (SBIC). Currently, he is Divisional Director at A*STAR’s Institute of Molecular and Cell Biology (IMCB), and Professor at the National University of Singapore (NUS) and Duke-NUS Medical School.

This article was made for A*STAR Research by Wildtype Media Group