Abstract
Abstract Differential metabolomic alterations occur during prostate cancer progression. Exploring the metabolome of prostate cancer progression, may lead to the identification of critical biomarkers for cancer invasion and disease aggressiveness. Recently, we have identified sarcosine, an N-methyl derivative of the amino acid glycine, as a key metabolite increased most robustly in metastatic prostate cancer and detectable in the urine of men with organ-confined disease (Sreekumar et al., Nature, 2009). Here, we examined if the proximal regulatory enzymes of sarcosine, glycine-N-methyl transferase (GNMT), sarcosine dehydrogenase (SARDH) and pipecolic acid oxidase (PIPOX), play a functional role in prostate cancer progression. By tissue microarray analysis, we observed that GNMT protein levels are strongly associated with prostate cancer aggressiveness. Here, we demonstrate that stable knockdown of GNMT inhibits cell proliferation, induces apoptosis, attenuates cell invasion in Matrigel coated transwells, and blocks the anchorage-independent growth of the cancerous DU145 cells. Overexpression of GNMT in benign RWPE cells showed significantly increased cell invasion and increased sarcosine level. Importantly, knockdown of GNMT in DU145 cells also inhibited intravasation using chick chorioallantoic membrane (CAM) assay and tumor growth in xenograft assays. In contrast, we also showed that while the knockdown of sarcosine degrading enzymes, SARDH and PIPOX, induced invasion and increased sarcosine level in RWPE cells, the overexpression of these enzymes attenuated invasion and decreased sarcosine level. Further, overexpression of SARDH inhibited cell proliferation, blocked the anchorage-independent growth and also inhibited intravasation using CAM assay. Taken together, this study shows that the components of the sarcosine pathway may have potential as biomarkers of prostate cancer progression and serve as new avenues for therapeutic intervention. 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 2803. doi:10.1158/1538-7445.AM2011-2803
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