Supplementing Tyrosine to Enhance Chemotherapy Effectiveness

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Supplementing Tyrosine to Enhance Chemotherapy Effectiveness

Supplementing Tyrosine to Enhance Chemotherapy Effectiveness

Chemotherapy based on genotoxic drugs is the most widely used cancer treatment in clinical practice. However, variations in chemotherapy drug sensitivity are frequently observed among different patients and at different stages of treatment.

There is a pressing need in clinical practice to better understand the biological basis of genotoxic chemotherapy sensitivity, in order to provide precise treatment strategies for patients.

Recent research has highlighted the significant impact of amino acid metabolism on the prognosis of cancer patients. For instance, methionine metabolism significantly affects tumor progression, reducing dietary methionine can effectively inhibit tumor growth, and enhance anti-tumor immunity. More and more studies suggest that targeting amino acid metabolism has immense potential to improve cancer treatment. However, the utilization of amino acid metabolism pathways to enhance chemotherapy effectiveness is still largely unexplored.

On October 26, 2023, a team of researchers from Sun Yat-sen University published a research paper titled “Tyrosine catabolism enhances genotoxic chemotherapy by suppressing translesion DNA synthesis in epithelial ovarian cancer” in the journal Cell Metabolism.

Using an ovarian cancer disease model, the team discovered for the first time that tyrosine catabolism significantly enhances the effectiveness of chemotherapy and revealed the molecular mechanisms through which tyrosine catabolism product, fumarate, suppresses translesion DNA synthesis (TLS), thereby promoting sensitivity to genotoxic chemotherapy drugs.

This provides essential theoretical support for the clinical application of dietary tyrosine to improve chemotherapy effectiveness.

Supplementing Tyrosine to Enhance Chemotherapy Effectiveness

The research team primarily used ovarian cancer as their disease model. They initially employed an amino acid metabolism-related gene shRNA library for screening and found that intervening in tyrosine catabolism can inhibit DNA damage caused by genotoxic chemotherapy drugs. Fumarylacetoacetate hydrolase (FAH) catalyzes the final step of tyrosine catabolic pathway, and knocking down FAH significantly reduces chemotherapy-induced DNA damage and cell apoptosis. The team conducted clinical relevance analysis using TCGA databases and samples from ovarian cancer patients, revealing a close correlation between FAH expression in tumor cells and chemotherapy sensitivity.

Further research by the team through various molecular and cell biology techniques showed that genotoxic drugs induce metabolic reprogramming in ovarian cancer tumor cells under chemotherapy pressure, leading to increased intracellular reactive oxygen species levels.

This results in suppressed mitochondrial aerobic oxidation, massive anaerobic oxidation of glucose with lactate production, glutamine supplementation of TCA cycle metabolites through glutaminolysis, and glutamine carboxylation.

These glutamine metabolism-related pathways generate fumarate as a major intermediate metabolic product in both the cytoplasm and mitochondria. FAH-mediated tyrosine catabolism is the primary source for supplementing the nuclear fumarate pool. Under chemotherapy pressure, increased intracellular oxygen levels in tumor cells lead to FAH being oxidized at methionine residues, allowing it to enter the nucleus.

Nuclear FAH is recruited to chromatin and produces fumarate. Molecular dynamics simulations and in vitro biochemical experiments demonstrated that FAH-generated fumarate can directly bind to the REV1 R516 site, inhibiting the interaction between REV1 and REV7, thereby suppressing TLS.

Supplementing Tyrosine to Enhance Chemotherapy Effectiveness

FAH expression exhibits a significant downward trend in ovarian cancer tumor tissues and continues to decrease with disease progression, which may lead to a downregulation of tyrosine catabolism flow and reduced chemotherapy sensitivity. The team’s research in an ovarian cancer mouse model revealed that supplementing tyrosine in the diet significantly improves chemotherapy effectiveness and reduces the risk of chemotherapy resistance, especially in tumors with low FAH expression.

In summary, this study has uncovered a new mechanism of tyrosine catabolism regulation on chemotherapy sensitivity. It reveals that under chemotherapy pressure, fumarate, a metabolite of tyrosine catabolism, suppresses translesion DNA synthesis by binding to REV1 in the nucleus, which provides a vital strategy for improving chemotherapy in ovarian cancer patients through dietary tyrosine supplementation. Further clinical trials are needed to validate this approach.

The authors of this research include Chao Yun Pan, Shuzhong Yao, Junxiu Liu, Jie Li, Cuimiao Zheng, and Qiuwen Mai, with Chao Yun Pan being the corresponding author. The Pan lab at Sun Yat-sen University primarily focuses on ovarian cancer as a disease model, studying the critical role of metabolism in cell cycle checkpoints and DNA replication stress regulation, and exploring the mechanisms of genotoxic chemotherapy resistance and reversal strategies. Their research findings have been published in journals such as Cell Metabolism, JCI, and Oncogene. The Pan lab is currently recruiting postdoctoral researchers, and interested individuals are welcome to contact Dr. Chao Yun Pan for more information.

Link to the full research paper