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Published on: June 13, 2014
Argininosuccinate lyase is a potential therapeutic target in breast cancer
Hau-Lun Huang1, Wei-Ching Chen1, Hui-Ping Hsu2
1Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City 701, Taiwan, R.O.C.
Abstract:
Arginine is a non-essential amino acid that modulates nitric oxide production and cancer homeostasis. In our previous study, we observed that blocking argininosuccinate lyase (ASL) attenuates tumor progression in liver cancer. However, the role of ASL in human breast cancer has been studied to a lesser degree. In the present study, we investigated the effect of targeting ASL in breast cancer. We found that ASL was induced by ER stress and was significantly upregulated in breast cancer tissues compared to that in the corresponding normal tissues. Downregulation of ASL inhibited the growth of breast cancer in vitro and in vivo. The level of cell cycle-related gene, cyclin A2, was reduced and was accompanied by a delay in G2/M transition. ASL shRNA-induced cell inhibition was rescued by exogenous cyclin A2. Furthermore, autophagy was observed in the cells expressing ASL shRNA, and inhibition of autophagy reduced cell growth, indicating that autophagy played a cell survival role in the ASL knockdown cells. Moreover, inhibition of ASL reduced NO content. Introduction of the NO donor partially restored the growth inhibition by ASL shRNA. Thus, the mechanism induced by ASL shRNA which occurred in human breast cancer may be attributed to a decrease in cyclin A2 and NO.
Insights
Targeting argininosuccinate lyase (ASL) in breast cancer inhibits tumor growth by reducing cyclin A2 and nitric oxide (NO) levels. This study reveals ASL as a potential therapeutic target for breast cancer treatment.
Area of Science:
- Biochemistry
- Oncology
- Molecular Biology
Background:
- Arginine is a non-essential amino acid crucial for nitric oxide (NO) production and cancer homeostasis.
- Argininosuccinate lyase (ASL) has been shown to affect tumor progression in liver cancer.
- The specific role of ASL in human breast cancer remains less understood.
Purpose of the Study:
- To investigate the effect of targeting ASL in human breast cancer.
- To elucidate the molecular mechanisms underlying ASL's role in breast cancer progression.
Main Methods:
- ASL expression analysis in breast cancer tissues.
- In vitro and in vivo studies involving ASL downregulation using ASL shRNA.
- Cell cycle analysis and assessment of autophagy.
- Measurement of nitric oxide (NO) levels.
Main Results:
- ASL is upregulated in breast cancer tissues and induced by ER stress.
- ASL downregulation inhibits breast cancer cell growth in vitro and in vivo.
- Reduced cyclin A2 levels and G2/M phase delay were observed upon ASL knockdown.
- Autophagy was induced and played a cell survival role in ASL-depleted cells.
- ASL inhibition decreased NO production, and NO supplementation partially rescued growth inhibition.
Conclusions:
- ASL is a significant factor in human breast cancer progression.
- Targeting ASL may represent a novel therapeutic strategy for breast cancer.
- The anti-tumor effects of ASL inhibition are mediated by decreased cyclin A2 and NO levels, alongside induced autophagy.
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