We have previously identified an
androgen-responsive gene in rat prostate that shares homology with the aci-
reductone dioxygenase (ARD/ARD') family of
metal-binding
enzymes involved in
methionine salvage. We found that the gene, aci-
reductone dioxygenase 1 (ADI1), was downregulated in
prostate cancer cells, whereas enforced expression of rat Adi1 in these cells caused apoptosis. Here we report the characterization of human ADI1 in
prostate cancer.
Androgens induced ADI1 expression in human
prostate cancer LNCaP cells, which was not blocked by
cycloheximide, indicating that ADI1 is a primary
androgen-responsive gene. In human
benign prostatic hyperplasia specimens, epithelial cells expressed ADI1. Immunohistochemistry of prostate
tumor tissue microarrays showed that benign regions expressed more ADI1 than
tumors, suggesting a suppressive role for ADI1 in
prostate cancer.
Bacterial lysates containing recombinant ADI1 produced a five-fold increase in aci-
reductone decay over controls, demonstrating that ADI1 has ARD activity. We generated point mutations at key residues in the
metal-binding site of ADI1 to disrupt ARD function, and we found that these mutations did not affect intracellular localization, apoptosis, or colony formation suppression in human
prostate cancer cells. Collectively, these observations argue that ADI1 may check
prostate cancer progression through apoptosis and that this activity does not require
metal binding.