HealthDay News — Loss of argininosuccinate synthetase 1 (ASS1), a key enzyme for arginine synthesis, occurs in invasive bladder cancer, according to a study published online in The American Journal of Pathology.
Noting that loss of ASS1 occurs in many cancers, making them targetable by the arginine-degrading enzyme pegylated arginine deiminase (ADI-PEG 20), Divya Sahu, PhD, from the University of California at San Diego, and colleagues examined the expression and effects of ASS1 loss in bladder cancer.
The researchers identified ASS1 loss in conventional and micropapillary urothelial, small cell, and squamous cell carcinoma subtypes of invasive bladder cancer, and in T24, J82, and UM-UC-3 cell lines; ASS1 loss was not seen in 5637, RT112, and RT4 cell lines. ASS1-deficient cells were preferentially sensitive to ADI-PEG 20, with reduced colony formation and cell viability and increased sub-G1 fractions. General control nonderepressible 2-dependent eukaryotic initiation factor 2α phosphorylation was induced by ADI-PEG 20, as was activating transcription factor 4 and C/EBP homologous protein up-regulation, which correlated with caspase-independent apoptosis and autophagy. Selective siRNA silencing of these proteins ablated these effects. These effects were reversed by ASS1 overexpression in UM-UC-3 or ASS1 silencing in RT112 cells. In UM-UC-3 xenografts, ADI-PEG 20 treatment correlated with a reduction in tumor number and a decrease in Ki-67 proliferation.
“This suggests that ASS1 loss occurs in invasive bladder cancer and is targetable by ADI-PEG 20,” the authors write.
One author disclosed financial ties to Polaris Pharmaceuticals, which supplied the drug ADI-PEG 20.
- Sahu D, Gupta S, Hau AM, et al. Argininosuccinate Synthetase 1 Loss in Invasive Bladder Cancer Regulates Survival through General Control Nonderepressible 2 Kinase–Mediated Eukaryotic Initiation Factor 2α Activity and Is Targetable by Pegylated Arginine Deiminase. Am J Pathol. 12 December 2016. DOI: http://dx.doi.org/10.1016/j.ajpath.2016.09.004