Arginine’s Metabolic Role in Hepatocellular Carcinoma

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Cancer is a complex and multifaceted disease that has challenged researchers for decades. In recent years, significant advancements have shed light on the underlying mechanisms of cancer, revealing it to be more than just uncontrolled cell growth.

It is now understood that cancer is, in fact, a metabolic disorder in which several major metabolic pathways are rewired to enhance cell proliferation.

This reprogramming includes alterations in carbohydrate, amino acid, nucleotide, fatty acid, and lipid metabolism. However, the precise upstream triggers and downstream consequences of metabolic reprogramming in cancer remain largely unknown, making it a critical area of investigation in the field of oncology.

Amino Acid Metabolism in Cancer

One of the metabolic pathways frequently rewired in cancer is amino acid metabolism. This reprogramming has far-reaching implications for tumor growth and progression. For instance, argininosuccinate synthetase 1 (ASS1), a rate-limiting enzyme in arginine synthesis, often exhibits altered expression patterns in various tumors.

Some cancers, such as colon, lung, gastric, and ovarian cancer, exhibit overexpression of ASS1, while others like renal cell carcinoma (RCC), melanoma, prostate cancer, and hepatocellular carcinoma (HCC) show a loss of ASS1. Despite the focus on ASS1, little was known about the levels of arginine in tumors until recently.

Arginine’s Versatility and Impact on Tumorigenesis

Arginine is a versatile amino acid with several roles in cellular physiology. It serves as a fundamental building block in protein synthesis, a precursor for polyamines, creatine, and nitric oxide. Moreover, arginine can interconvert with proline and glutamate and activate mTORC1, a key regulator of cell growth. Recent evidence also suggests that arginine can influence metabolism independently of mTORC1. Additionally, arginine is a product of the urea cycle, in which ASS1 plays a critical role.

Arginine in Hepatocellular Carcinoma (HCC)

Researchers have recently investigated the role of arginine in hepatocellular carcinoma (HCC), a prevalent form of liver cancer. Surprisingly, their findings showed that arginine levels are elevated in HCC, even though arginine synthesis is suppressed. This intriguing phenomenon was attributed to increased arginine import and reduced arginine-to-polyamine conversion by the enzymes arginase 1 (ARG1) and agmatinase (AGMAT). The high arginine levels were found to reprogram metabolism, promoting tumorigenicity in HCC cells.

RBM39: A Key Player in Arginine-Mediated Metabolic Reprogramming

The study also unveiled the role of RNA-binding protein RBM39 in arginine-mediated metabolic reprogramming in HCC. Arginine was found to bind to RBM39, regulating the expression of metabolic genes. Notably, RBM39 was shown to promote the expression of asparagine synthetase (ASNS), a critical enzyme in asparagine synthesis. Asparagine, in turn, enhanced arginine uptake, establishing a positive feedback loop that sustains high arginine levels and supports oncogenic metabolism.

Arginine’s Impact on Immune Escape and Tumor Growth

The parallels between arginine’s role in cancer and T cell activation are striking. T cells require arginine for activation, and it was observed that supraphysiological levels of arginine can modulate metabolism, favoring oxidative phosphorylation and nucleotide synthesis. However, in contrast to T cells, cancer cells reduce arginine-to-polyamine conversion, maintaining elevated levels of unmetabolized arginine. This may contribute to immune evasion by tumors and enhance their growth.

Mechanisms of RBM39-Mediated Regulation

The study proposes that RBM39 acts as an arginine-binding regulator of metabolic genes, including ASNS, in HCC. RBM39 can function as a pre-mRNA splicing factor or a transcription coactivator or co-repressor, depending on its interacting proteins. Depletion of RBM39 or restriction of arginine led to impaired transcription but not splicing of metabolic genes, indicating that RBM39 controls gene expression at the transcriptional level. Further research is needed to identify potential transcription regulators that interact with RBM39, possibly in an arginine-dependent manner.

The N-Terminus of RBM39: A Regulatory Nexus

The study highlights that arginine binds to the structurally unresolved N-terminal region of RBM39, which is presumed to be disordered. This region is known to be regulated by tyrosine kinase c-Abl, which phosphorylates residues to enhance transcriptional coactivation by RBM39. Thus, the N-terminus of RBM39 may serve as a crucial regulatory region integrating various inputs, including phosphorylation and arginine binding.

Arginine in Embryonic Development and Cancer

Interestingly, the study found that ASNS and RBM39 expression is high in developing embryonic liver but low in adult liver. This suggests that the expression of these genes may reflect an embryonic metabolic state that is reactivated in HCC, aligning with the notion that cancer cells often exhibit dedifferentiation.

Therapeutic Implications

Finally, the study explores the potential therapeutic implications of targeting arginine-mediated metabolic reprogramming in cancer. Traditional approaches involving arginine-degrading enzymes have shown limited clinical benefit. However, the findings suggest an alternative strategy of targeting cancer-specific arginine-binding factors like RBM39, rather than broadly limiting arginine in circulation.

This approach could spare T cells, which require arginine for activation, and might be more effective in HCC patients with specific molecular profiles. The use of aryl sulfonamides to degrade RBM39 warrants further investigation as a promising therapeutic avenue for HCC.

Conclusion

In conclusion, the last decade has witnessed significant progress in understanding the role of arginine in cancer metabolism, particularly in hepatocellular carcinoma. The findings have illuminated the intricate mechanisms by which arginine reprograms metabolic pathways, promotes tumorigenicity, and interacts with RBM39 to regulate gene expression.

These discoveries offer new avenues for therapeutic interventions in liver cancer and potentially other malignancies, bringing us closer to unlocking the secrets of cancer metabolism and improving patient outcomes in the fight against this devastating disease.


reference link : https://www.cell.com/cell/fulltext/S0092-8674(23)01032-2#secsectitle0085

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