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.

Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

“…Conversely, in some ASS1-negative tumors an abnormally increased ASL expression can be found [33]. This is accompanied by higher clinical aggressiveness mediated by NO and cyclin A2 [34].…”

Arginine and the metabolic regulation of nitric oxide synthesis in cancer

“…In samples from colon and breast cancer patients, the overexpression of ASL , which encodes the enzyme that synthesizes arginine, is associated with poor survival (Huang et al, 2015, 2017a). Additionally, tumor samples from hepatocellular carcinoma patients show increased ASL expression and, in human colon, breast and hepatocellular carcinoma cells, silencing of ASL expression by short-hairpin RNA, or the reduction of NO production by a NOS inhibitor, inhibited cancer cells' proliferation and anchorage-independence (Box 1) (Huang et al, 2013, 2015, 2017a). These studies imply that ASL exerts its tumorigenic effects at least in part through NO, but they do not rule out the possibility that increased arginine levels might promote cancer by supporting the synthesis of other arginine-derived molecules, such as polyamines.…”

Molecular basis and current strategies of therapeutic arginine depletion for cancer

“…However, in 5 of 22 primary glioblastoma cultures studied by Syed et al ., a CpG island in the ASL‐1 core promoter is significantly methylated leading to downregulation of ASL‐1 mRNA . Contrastingly, expression of ASL‐1 is abnormally increased in some arginine‐dependent, ASS‐1 negative tumors such as breast and liver cancer cells . Blocking ASL‐1 expression using anti ASL‐1 shRNA in these cells leads to the induction of autophagy and downregulation of cell growth.…”

“…12 Contrastingly, expression of ASL-1 is abnormally increased in some argininedependent, ASS-1 negative tumors such as breast and liver cancer cells. 13 Blocking ASL-1 expression using anti ASL-1 shRNA in these cells leads to the induction of autophagy and Overall, median survival was 11.4 months. An increased antibody production to ADI-PEG observed after the first 4 weeks, which correlated with increasing arginine levels downregulation of cell growth.…”