Key Takeaways & Executive Findings
- •• LM2I, a specific activator of ASS1, suppresses liver cancer by promoting CAD ubiquitination and degradation, thereby inhibiting pyrimidine synthesis. • ASS1 and CAD expression are negatively correlated in liver cancer, and LM2I is more effective in low-ASS1-expressing cells. • LM2I exhibits antitumor activity in vivo and in vitro with no observed toxicity in mice, highlighting its therapeutic potential. • Pyrimidine supplementation rescues LM2I-induced proliferation inhibition, confirming the mechanistic link between ASS1 activation and pyrimidine metabolism.
Abstract
The urea cycle occurs mainly in the liver and undergoes changes during hepatocarcinogenesis. Argininosuccinate synthase 1 (ASS1) is a key enzyme in the urea cycle and is expressed at low levels in certain cancers. LM2I, a specific activator of ASS1, exhibits significant antitumor activity. However, the antitumor mechanism of LM2I in liver cancer remains unclear. In this study, we find that LM2I is more effective for liver cancer cells with low ASS1 expression. The results of the IP-LC/MS experiments reveal that ASS1 interacts with CAD. The expressions of ASS1 and CAD in liver cancer tissues and cells are negatively correlated. LM2I promotes the ubiquitination of CAD protein through ASS1. LM2I inhibits the proliferation of liver cancer cells in vivo and in vitro. However, its efficacy is weak in liver cancer cells stably overexpressing CAD. The H&E staining results reveal that LM2I has no toxicity in mice. In terms of metabolism, LM2I increases the urea content and decreases the pyrimidine content in liver cancer cells. Overexpression of CAD can reduce the inhibitory effect of LM2I on pyrimidine. Pyrimidine supplementation facilitates the proliferation of liver cancer cells, particularly when they are treated with LM2I. In summary, ASS1 interacts with CAD, and LM2I enhances CAD degradation through the activation of ASS1, consequently inhibiting pyrimidine synthesis and the progression of liver cancer.
1. Introduction
LM2I, a derivative of spinosad A (SPA) which is a metabolic product of Saccharopolyspora spinosa, exhibits significant antitumor activity [1]. SPA is characterized by a distinctive tetracyclic structure that is linked to two different six-membered sugar rings [2]. It serves as the active component in numerous registered pesticides and certain FDA-approved pharmaceuticals [3]. SPA is known for its high degree of contact and gastric toxicity against harmful insects [4,5], while exhibiting low toxicity in mammals [6]. However, the limited water solubility (0.235 ± 0.13 mg/mL) of SPA poses challenges for its formulation as a clinical drug. Consequently, we synthesized a series of SPA derivatives and identified LM2I, which has favorable water solubility (10.87 ± 0.34 mg/mL) and exhibits antitumor activity [1]. Research has indicated that LM2I, a specific activator of ASS1, effectively inhibits triple-negative breast cancer (TNBC) and colon cancer growth [1,7].
According to the International Agency for Research on Cancer (IARC), 20 million new cancer cases were diagnosed globally in 2022 [8]. Liver cancer ranks sixth worldwide in incidence and third in mortality, with 865,269 new cases and 757,948 deaths [8]. The development of liver cancer is strongly influenced by external environmental factors, such as hepatitis B/C viruses, alcohol and aflatoxin [9]. In East Asia, such as China, Japan and Korea, liver cancer is most prevalent and deadly [10]. Surgical approaches and percutaneous ablative therapies are recommended as treatment options for curing liver cancer but not for advanced liver cancer patients [11,12]. Therefore, identification of effective targets and drugs for liver cancer is urgently needed.
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Zhengnan Ming, Tiao Luo, Zizheng Zou, Wensong Luo, Xiyuan Hu, Ling Chen, Jiang Zhou, Xiaohe Liu, Mingquan Liu, Jijia Li, Dayou Ma, Suyou Liu, Zhiyong Luo (2026). LM2I leads to CAD ubiquitination and liver cancer suppression through activation of ASS1. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025083
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Frequently Asked Questions
What is the role of LM2I in liver cancer treatment?
LM2I is a specific activator of ASS1 that suppresses liver cancer by promoting the ubiquitination and degradation of CAD, thereby inhibiting pyrimidine synthesis and cancer cell proliferation.
How does ASS1 interact with CAD in liver cancer?
ASS1 interacts with CAD, and their expressions are negatively correlated in liver cancer tissues and cells. LM2I enhances this interaction, leading to CAD ubiquitination and degradation.
What is the significance of pyrimidine synthesis in liver cancer?
Pyrimidine synthesis is essential for cell proliferation. LM2I reduces pyrimidine content by degrading CAD, and pyrimidine supplementation can rescue the inhibitory effect, highlighting its importance in liver cancer progression.
Is LM2I toxic to normal cells?
H&E staining results in mice indicate that LM2I has no toxicity, suggesting a favorable safety profile for potential therapeutic use.
What are the clinical implications of this study?
The study identifies LM2I as a promising therapeutic agent for liver cancer, particularly for tumors with low ASS1 expression, and provides mechanistic insights into targeting pyrimidine metabolism.
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