Invasive Bladder CA Tied to Loss of Key Enzyme

ASS1-deficient cells were preferentially sensitive to ADI-PEG 20, as shown by reduced cell viability
ASS1-deficient cells were preferentially sensitive to ADI-PEG 20, as shown by reduced cell viability

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. 

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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.

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