title: Argininosuccinate lyase is a potential therapeutic target in breast cancer.
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.
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City 701, Taiwan, R.O.C.
authors.forename: Hau-Lun
authors.initials: HL
authors.lastname: Huang
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City 701, Taiwan, R.O.C.
authors.forename: Wei-Ching
authors.initials: WC
authors.lastname: Chen
authors.affiliation: Department of Surgery, College of Medicine, National Cheng Kung University, Tainan City 701, Taiwan, R.O.C.
authors.forename: Hui-Ping
authors.initials: HP
authors.lastname: Hsu
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City 701, Taiwan, R.O.C.
authors.forename: Chien-Yu
authors.initials: CY
authors.lastname: Cho
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City 701, Taiwan, R.O.C.
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Hung
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City 701, Taiwan, R.O.C.
authors.forename: Chih-Yang
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City 701, Taiwan, R.O.C.
authors.forename: Ming-Derg
authors.initials: MD
authors.lastname: Lai
mesh_terms: D001120:Arginine / Q000235:genetics; D001123:Argininosuccinate Lyase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D001343:Autophagy / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D056751:Cyclin A2 / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D034741:RNA, Small Interfering
chemical_list: D056751:Cyclin A2; D034741:RNA, Small Interfering; D009569:Nitric Oxide; D001120:Arginine; D001123:Argininosuccinate Lyase