Abstract 5541: The dual effects of H6D polymorphism of NAG-1/GDF15 in prostate cancer carcinogenesis

Abstract

Abstract Nonsteroidal anti-inflammatory drug-activated gene (NAG-1) is a divergent member of the transforming growth factor beta superfamily. NAG-1 has been implicated in many cellular processes, including inflammation, early bone formation, apoptosis, and tumorigenesis, in several types of cancers. Evidence from recent clinical studies suggests that a C to G single nucleotide polymorphism at position 6 (histidine to aspartic acid substitution, or H6D (G) of the NAG-1 protein is associated with lower incidence, but higher rate of mortality, of prostate cancer. The objective of the current study was to determine the activity of the NAG-1 H6D variant in prostate cancer using two different approaches. First, DU145 cells stably transfected with the H6D NAG-1 gene, wild-type NAG-1 gene, and empty pLXIN vector were injected into nude mice subcutaneously and tumor growth monitored for eight weeks. The H6D variant was less tumorigenic than the wild-type NAG-1, and significantly inhibited tumor growth, 67% by volume and 59% by tumor weight compared to control mice. The growth inhibition by the H6D variant of NAG-1 was associated with significant reduction of serum levels of adiponectin, leptin, and IGF-1, and expression of Cyclin D1 in tumor samples. Second, we examined whether the sequence variant in the NAG-1 gene was associated with prostate cancer tumor aggressiveness in blood samples from the North Carolina-Louisiana Prostate Cancer Project (PCaP). A total of 449 Caucasians Americans and 413 African Americans were examined for allele frequencies using Taqman SNP genotyping assay. Although statistically insignificant, African Americans carrying the H6D (G) allele had an increased risk of more aggressive prostate cancer than those carrying two copies of the C allele (Odds ratio, 1.63; 95% CI, 0.903-2.95; P = 0.25). This result may help to explain the higher mortality rate of prostate cancer in African Americans. In conclusion, our data suggest that the H6D polymorphism of NAG-1 may have a dual effect during the early and late stages of prostate cancer carcinogenesis. More studies are needed to further examine the association of H6D variant of NAG-1 with prostate cancer incidence and progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5541. doi:10.1158/1538-7445.AM2011-5541