Arginine-Driven Metabolic Reprogramming in Liver Cancer: A Potential Therapeutic Target

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Arginine-Driven Metabolic Reprogramming in Liver Cancer: A Potential Therapeutic Target

Arginine-Driven Metabolic Reprogramming in Liver Cancer: A Potential Therapeutic Target

Cancer as a Metabolic Disease: Study in Cell Reveals Arginine Drives Metabolic Reprogramming to Promote Liver Cancer Growth.

The liver is a vital organ with many functions, including nutrient metabolism, energy storage, blood sugar regulation, and detoxification. Liver cancer is one of the deadliest cancers globally. According to the International Agency for Research on Cancer (IARC), liver cancer ranks sixth in terms of incidence and third in terms of mortality among all cancers. China is the leading country in liver cancer cases, accounting for nearly half of the global incidence and mortality each year. Obesity, alcohol consumption, and hepatitis virus infection are highly associated with liver cancer incidence. Early diagnosis and appropriate treatment strategies are crucial for improving liver cancer treatment outcomes.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer, accounting for 90% of primary liver cancers. It is an aggressive malignant tumor that is difficult to diagnose early, progresses rapidly, and is often diagnosed at an advanced stage with few effective treatment options, resulting in a 5-year survival rate of only about 15-18%.

Cancer cells are like “chameleons,” able to completely change their metabolism to sustain growth. Recently, scientists from the University of Basel in Switzerland discovered that high levels of the amino acid arginine drive metabolic reprogramming, promoting tumor growth. This research provides a new avenue for improving liver cancer treatment.

Published in the prestigious academic journal Cell on October 6, 2023, the study titled “Arginine reprograms metabolism in liver cancer via RBM39” sheds light on how cancer cells alter their metabolism and how these changes contribute to tumor formation.

Arginine-Driven Metabolic Reprogramming in Liver Cancer: A Potential Therapeutic Target

Cancer as a Metabolic Disease

In the past decade, scientists have made significant progress in understanding various aspects of cancer. Historically, cancer has been viewed as a disorder of cell proliferation.

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

So, how do cells change their metabolism, and how do these metabolic changes lead to tumor formation?

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

Accumulation of Arginine in Liver Cancer

Healthy liver cells gradually change their behavior when transformed into cancer cells. They reprogram their metabolism to grow as rapidly as possible, for example, consuming much more glucose than normal cells and enhancing nutrient uptake.

The study’s first author, Dr. Dirk Mossmann, stated, “We examined liver cancer samples from mice and patients 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 inhibiting its consumption. Furthermore, we found that high levels of arginine are necessary 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 found that high concentrations of arginine bind to specific factors and trigger 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, in which they can divide indefinitely.

Furthermore, tumor cells benefit from increased arginine uptake in another way. Our immune cells depend on arginine to function normally, so tumor cells’ uptake of arginine helps them evade the immune system.

Specifically, the study found that arginine levels are elevated in both mouse and human hepatocellular carcinoma (HCC), with tumor cells accumulating high levels of arginine due to increased uptake and decreased conversion of arginine to polyamines. Importantly, high levels of arginine promote tumor formation through further 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 leads to enhanced arginine uptake, forming a positive feedback loop to maintain high levels of arginine and oncogenic metabolism.

Therefore, arginine acts as a second messenger-like molecule, reprogramming 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 proposed a new 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 team used Indisulam to treat hepatocellular carcinoma, a carbonic anhydrase inhibitor that specifically degrades RBM39. The results showed that Indisulam induced RBM39 degradation and prevented metabolic reprogramming. Through this approach, adverse effects on the immune system due to reducing 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 conclusion, this study in mice, cells, and organoids derived from hepatocellular carcinoma patients demonstrates that arginine reprograms metabolism in liver cancer by binding to RBM39. This discovery provides a new biomarker for early diagnosis of liver cancer and a new target for its treatment.

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