Arginine-Driven Metabolic Reprogramming Promoting Liver Cancer Growth

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Arginine-Driven Metabolic Reprogramming Promoting Liver Cancer Growth

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Cancer Revealed as a Metabolic Disease: Study in Cell Uncovers Arginine-Driven Metabolic Reprogramming Promoting Liver Cancer Growth.

The liver, a vital organ in the human body, plays a crucial role in various essential functions such as metabolism of nutrients, energy storage, blood sugar regulation, as well as detoxification and removal of harmful substances and drugs.

Liver cancer stands as one of the deadliest cancers globally. According to the 2020 Global Cancer Burden data released by the International Agency for Research on Cancer (IARC), liver cancer ranks sixth in terms of incidence among all cancers, and third in terms of mortality.

Notably, factors like obesity, alcohol consumption, and hepatitis virus infections are strongly associated with the development of liver cancer. Early diagnosis and appropriate treatment strategies are critical for improving liver cancer outcomes.

Among the various types of liver cancer, Hepatocellular Carcinoma (HCC) is the most common, constituting 90% of primary liver cancers. It is an aggressive malignancy characterized by fast progression, making it challenging to diagnose in its early stages. Unfortunately, effective treatment options are limited for most patients diagnosed with HCC, resulting in a 5-year survival rate of only around 15-18%.

Cancer cells are like chameleons, capable of completely altering their metabolism to sustain continuous growth.

Recently, scientists at the University of Basel in Switzerland discovered that high levels of the amino acid arginine drive metabolic reprogramming, thus promoting tumor growth.

This groundbreaking research offers new avenues for improving liver cancer treatment.

Titled “Arginine Reprograms Metabolism in Liver Cancer via RBM39,” the study was published on October 6, 2023, in the prestigious academic journal Cell.

Cancer as a Metabolic Disease

Over the past decade, scientists have made significant strides in understanding various aspects of cancer. Historically, cancer has been regarded as a disorder of cell proliferation.

However, mounting evidence suggests that cancer is a metabolic disease. In other words, cancer arises when cells reset their metabolism to allow uncontrolled cell proliferation.

So, how do cells change their metabolism, and how does this metabolic shift lead to tumor formation?

In this Cell paper, a research team led by Professor Michael Hall at the University of Basel elucidates the key drivers of metabolic reprogramming in liver cancer cells.

Accumulation of Arginine in Liver Cancer

Healthy liver cells gradually alter their behavior when transforming into cancer cells. They reprogram their metabolism to grow as rapidly as possible, consuming much more glucose than normal cells and enhancing the uptake of nutrients.

Dr. Dirk Mossmann, the first author of the paper, stated, “We examined liver cell samples from mice and patients with liver cancer and found significantly elevated levels of arginine. However, cancer cells actually produce less or even no arginine. Cancer cells accumulate high levels of arginine by increasing its uptake and suppressing its consumption. Furthermore, we discovered that elevated arginine levels are essential for tumor development, independent of its role in protein synthesis.”

These findings raise a new question: how does arginine lead to tumor formation?

Role of Arginine in Tumor Growth

The study reveals that high concentrations of arginine bind to specific factors, triggering metabolic reprogramming by regulating the expression of metabolism-related genes to promote tumor growth. Under this metabolic reprogramming, tumor cells revert to an undifferentiated embryonic cell state, allowing them to divide indefinitely.

Additionally, tumor cells benefit from increased arginine intake in another way. Our immune cells depend on arginine to function properly; therefore, increased arginine uptake by tumors helps tumor cells evade the immune system.

Specifically, the research found that arginine levels increase in both mouse and human hepatocellular carcinoma (HCC) due to increased arginine uptake and reduced conversion of arginine into polyamines.

Importantly, high arginine levels further promote tumor formation through additional metabolic reprogramming, including changes in glucose, amino acid, nucleotide, and fatty acid metabolism.

Mechanistically, arginine regulates the expression of metabolism-related genes by binding to RNA binding motif protein 39 (RBM39). RBM39-mediated asparagine synthesis upregulation enhances arginine uptake, forming a positive feedback loop to maintain high arginine levels and oncogenic metabolism.

Therefore, arginine acts as a second messenger-like molecule that can reprogram metabolism to promote tumor growth.

Implications for Liver Cancer Diagnosis and Treatment

Can the role of arginine in promoting oncogenic metabolism be used for cancer diagnosis and treatment?

The research team proposes a novel treatment strategy—targeting cancer-specific arginine-binding factors (such as RBM39) instead of depleting arginine. This approach avoids adverse effects on T cells (which require arginine for activation).

The research team used Indisulam to treat hepatocellular carcinoma, a carbonic anhydrase inhibitor that specifically degrades RBM39. The results showed that Indisulam induces RBM39 degradation and prevents metabolic reprogramming. Through this approach, potential side effects on the immune system due to reduced overall arginine levels can be avoided.

Furthermore, metabolic changes, such as increased arginine levels, can serve as biomarkers for early cancer detection, which is crucial for successful cancer treatment and patient survival.

In summary, this research conducted in mice, cells, and liver cancer patients’ samples suggests that arginine reprograms metabolism in liver cancer by binding to RBM39. This discovery provides new biomarkers for early liver cancer diagnosis and opens up new targets for liver cancer treatment.

Arginine-Driven Metabolic Reprogramming Promoting Liver Cancer Growth

Paper Link:
https://www.cell.com/cell/fulltext/S0092-8674(23)01032-2

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