Researchers at have discovered that branched-chain amino acids (BCAAs) in tumours can be targeted to prevent and treat cancer. Together with collaborators from the United States and National Cancer Centre Singapore (NCCS), they found that some cancers potently suppress the catabolism (breakdown) of BCAAs. This leads to BCAAs accumulating in tumours and activating a known pro-oncogenic pathway called mTOR.
After identifying BCAA metabolism as a key pathway specific to liver cancer, they proceeded to find similar changes in stomach, colorectal, and kidney cancers, amongst others. Worldwide, cancer is the second leading cause of death, with stomach, colorectal and liver cancers accounting for some of the most common causes of cancer deaths.
Suppression of BCAA Catabolism as a Driver of Liver Cancer Development
The team found that the catabolism of BCAAs was not only suppressed in tumours when compared to adjacent normal tissue, but the degree of suppression correlated with tumour aggressiveness and disease progression. They also identified three BCAA catabolic enzymes—BCKDHA, ACADS, and ACADSB that were the best predictors of patient survival.
The changes in BCAA metabolism were confirmed by analysing metabolite and protein levels, as well as enzyme activity in the matching tumour and non-tumour liver samples. Using a new hyperpolarised magnetic resonance spectroscopy method developed by the SBIC researchers, enzyme activity in the livers of live subjects was monitored in real-time.
This non-invasive technique could eventually be used in the clinical setting to screen patients for changes in BCAA catabolism. By comprehensively analysing additional cancer subtypes profiled by TCGA, the investigators also found that reduced expression of BCAA catabolic enzymes correlated with tumour development, progression and aggressiveness, as well as patient survival in numerous other cancers.
Dietary BCAA Intake Linked to Tumour Development and Growth
Given that BCAAs are essential amino acids—meaning they are absorbed from food rather than produced naturally in the body—the researchers also explored how dietary BCAA intake influenced tumour development and growth. In the study, the researchers used a common mouse model of liver cancer, and fed the mice diets with either normal or high levels of BCAAs. After five to eight months, the group of mice fed with high BCAA diets had a potent increase in tumour number and size.
Dr. Han Weiping said, "The current study presents opportunities for the development of prevention and therapeutic intervention strategies to treat several common and deadly cancers. We hope to see that our study eventually leads to new drugs and therapies that benefit patients."
"This important study by Dr. Han Weiping's team is key in better understanding the role of the interesting cancer-driving metabolites, BCAAs—not only for liver cancer, but also potentially in other cancers. The finding that dietary BCAAs regulate cellular metabolism uncovers new factors in the cause of liver cancer, and potentially new drug targets," said Associate Professor Toh Han Chong.