Induction of human arylamine N-acetyltransferase type I by androgens in human prostate cancer cells.
Human arylamine N-acetyltransferases (NAT) bioactivate arylamine and heterocyclic amine carcinogens present in red meat and tobacco products. As a result, factors that regulate expression of NATs have the potential to modulate cancer risk in individuals exposed to these classes of carcinogens. Because epidemiologic studies have implicated well-done meat consumption as a risk factor for prostate cancer, we have investigated the effects of androgens on the expression of arylamine N-acetyltransferase type I (NAT1). We show that NAT1 activity is induced by R1881 in androgen receptor (AR)-positive prostate lines 22Rv1 and LNCaP, but not in the AR-negative PC-3, HK-293, or HeLa cells. The effect of R1881 was dose dependent, with an EC(50) for R1881 of 1.6 nmol/L. Androgen up-regulation of NAT1 was prevented by the AR antagonist flutamide. Real-time PCR showed a significant increase in NAT1 mRNA levels for R1881-treated cells (6.60 +/- 0.80) compared with vehicle-treated controls (1.53 +/- 0.17), which was not due to a change in mRNA stability. The increase in NAT1 mRNA was attenuated by concurrent cycloheximide treatment, suggesting that the effect of R1881 may not be by direct transcriptional activation of NAT1. The dominant NAT1 transcript present following androgen treatment was type IIA, indicating transcriptional activation from the major NAT1 promoter P1. A series of luciferase reporter deletions mapped the androgen responsive motifs to a 157-bp region of P1 located 745 bases upstream of the first exon. These results show that human NAT1 is induced by androgens, which may have implications for cancer risk in individuals.
Butcher
Neville J
NJ
School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland 4072, Australia. n.butcher@uq.edu.au
Tetlow
Natasha L
NL
Cheung
Catherine
C
Broadhurst
Gysell M
GM
Minchin
Rodney F
RF
D001191:Arylamine N-Acetyltransferase / Q000096:biosynthesis*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004790:Enzyme Induction / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis*; D008297:Male; D015741:Metribolone / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D014158:Transcription, Genetic
D007527:Isoenzymes; D011944:Receptors, Androgen; D015741:Metribolone; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1