p53 is the most mutated gene in human tumors, and its mechanism of tumor inhibition is still unknown. After years of research, it has been found that the loss of p53 can cause changes in different metabolic pathways. However, the current understanding of p53's mechanism of regulating metabolism and inhibiting tumors is still very limited, and it is necessary to continue to study in depth.
As the important role of p53 in metabolic regulation is gradually revealed, it can be speculated that by influencing different metabolic modes, the deletion and mutation of p53 can give tumor cells the ability to cope with a variety of different genetic mutations and metabolic pressures, improving the ability of tumor cells to survive and proliferate.
On April 9, 2020, the Jiang Peng Research Group of the School of Life Sciences of Tsinghua University published a paper in nature communications magazine titled: p53-mediated control of aspartate-asparagine homeostasis dictates LKB1 activity and modulates cell Survival (p53 affects LKB1 activity and tumor cell survival by regulating asparagine-aspartate homeostasis).
The study found that the deletion of p53 raised serum asparagine levels in mice, and the latter had the function of promoting the proliferation and survival of lymphoma cells; this finding partly explained the confusing phenomenon that most p53-deficient mice were susceptible to lymphoma.
In response to different stress stimuli and the need to meet rapid proliferation, tumor cells often alter the activity of certain metabolic pathways or levels of metabolites; and these abnormal changes in metabolism are often closely related to changes in the genetic background. A recent study by Jiang Peng's research group found that the deletion of p53 can lead to the reorganization of ammonia metabolism in tumor cells, which in turn accelerates the synthesis of polyamines and promotes the proliferation of tumor cells (Li et al. Nature, 2019）。
In this study, the researchers found that the deletion of p53 upregulated the expression of asparagine synthetase (ASNS), which affected the level of asparagine in the serum of mice, as well as the equilibrium state of asparagine and aspartate in the environment inside and outside tumor cells. The maintenance of homeostasis of asparagine and aspartic acid is critical to the fate-determining process of tumor cells. High levels of asparagine maintain the survival and proliferation of tumor cells, while removal of asparagine strongly inhibits the proliferation of tumor cells and leads to the occurrence of apoptosis.
To figure out how changes in the homeostasis of asparagine and aspartate affect the fate-determining process of tumor cells, the researchers conducted in vivo and in vitro molecular mechanism studies.
Levels of asparagine and aspartic acid were found to be perceived by the kinase LKB1. Asparagine and aspartic acid affect kinase activity of LKB1 and signaling of downstream AMPK signaling pathways by directly binding to LKB1. Interestingly, the binding of asparagine to LKB1 inhibits the activity of LKB1, while aspartic acid can enhance kinase activity of LKB1 to some extent.
Therefore, tumor cells control the activity of the LKB1-AMPK signaling pathway by regulating asparagine metabolism, achieving an impact on tumor cell survival and proliferation.
It is worth mentioning that the study shows that clinical first-line drugs that inhibit asparagine such as ASNase can be tried to treat p53 deficiency or mutant tumors. In addition, in mouse models, it has long been noted that although a variety of tumor lesions occur in p53-deficient mice, nearly 70% of p53-deficient mice die from lymphomas, and the reason for this has been an unsolved mystery.
This study found that the deletion of p53 increased serum asparagine levels in mice, and the latter had the function of promoting the proliferation and survival of lymphoma cells; this finding partly explained the confusing phenomenon that most p53-deficient mice were susceptible to lymphoma.
Deng Longfei, a 2014 doctoral student at the School of Life Sciences of Tsinghua University, is the first author. Jiang Peng, a researcher at the School of Life Sciences of Tsinghua University, is the corresponding author of the paper, and the research group of Professor Lan Xun of the School of Medicine of Tsinghua University gave great help to this research. The study was supported by the National Natural Science Foundation of China and CLS.
Thesis Link:
https://www.nature.com/articles/s41467-020-15573-6