New dawn for cancer metabolic treatment! TMU team’s research in arginine regulations of prostate cancer metabolism published in internationally renowned journal

Source: Taipei Medical University

Published on 2021-06-23

In the latest research by a team comprising members of TMU and the National Health Research Institutes, led by Academician Hsing-jen Kung (龔行健), it was discovered that prostate cancer, cells are addicted to arginine and use external arginine to reshape epigenetics to regulate the expression of mitochondrial proteins and maintain of mitochondria integrity to provide energy for survival.

Mitochondria is the power house of energy for the cell. If the external supply of arginine is cut off, the cancer cells will lose energy and starved to death, thus, achieving treatment goal.

The research team further discovered that oncogene TEAD4 plays an indispensable role in the arginine regulation of mitochondrial protein expression and function. The research paper, “Arginine is an epigenetic regulator targeting TEAD4 to modulate OXPHOS in prostate cancer cells”, was published in the world-renowned medical journal, Nature Communications on April 23, 2021.

According to statistics from the Ministry of Health and Welfare, the incidence and death rate of prostate cancer in Taiwan have been increasing yearly. Each year, more than 5,000 new cases are diagnosed. Prostatectomy and prostate irradiation therapy have a certain degree of curative effect on prostate cancer that has not yet metastasized. Yet, given that patients are predominantly seniors over 65 years old and postoperative complications include urinary incontinence and sexual dysfunction, passive hormonal therapy is still the widely accepted first-line treatment.

However, hormone therapy is not always curative, as some cancer cells become refractory to treatment and continue to grow. The condition of most patients will continue to deteriorate over time, resulting in the proliferation, metastasis and spread of the cancer cells. Therefore, to avoid over reliance on hormone therapy and take advantage of the specificity of the metabolic needs of tumor cells, the development of new treatment strategies has become imminently urgent.

According to Dr. Chia-ling Chen(陳嘉霖), it is currently believed that cancer is not only caused by genetic mutations, but also by epigenetic alterations. Therefore, targeting specific amino acids such as arginine which regulates cellular epigenetics offers opportunities to reprogram cancer genome and alter mitochondrial functions, leading to the demise of cancer cells.

Based on previous work, almost all prostate cancer cells express low level of ASS1, a key enzyme for arginine metabolism, and cannot synthesize their own arginine. By contrast, normal cells express abundant ASS1. Cancer cells, but not normal cells, must rely on arginine from outside the cell to maintain their livelihood. This is the basis of arginine-deprivation therapy. Arginine metabolizing enymes such as arginine deiminase (ADI) have been successfully used to starve cancer cells to death and are in clinical trials for certain cancers. Dr. Kung’s team found that dietary restriction of arginine is also effective in suppressing prostate cancer cell growth in preclinical models.

Compared to the widely used chemotherapy and radiation therapy, starvation therapy is mild with low side effects. In the future, arginine deprivation therapy may be combined with current hormone therapy to address the challenges facing the present prostate cancer.

The results of this research have impacts on both basic medicine and translational medicine research. In particular, it informs potential development of new cancer metabolic therapy which hopefully will help prostate cancer patients combat the threat of this dreadful disease.

Prostate cancer cells must rely on external arginine to maintain the normal functioning of their mitochondria, ” the powerhouse of the cell.

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