Abstract 3059: The Tmeff2 protein functions as a tumor suppressor and interacts with Sarcosine dehydrogenase

Abstract

Abstract Tmeff2 is a gene with an expression profile limited to the brain and the prostate but shown to be frequently upregulated in prostate cancer. It encodes a type I transmembrane protein with a short cytoplasmic tail containing a potential G-protein activation domain and an extracellular domain containing two follistatin (FS) modules and an epidermal growth factor-like (EGF) domain. Although these features are suggestive of a function in signal transduction, the role of the Tmeff2 in prostate cancer, or the mechanism(s) that lead to its overexpression during the disease are unclear. In the present study, we evaluated the functional role of Tmeff2 in prostate tumorigenesis. To investigate the function of the gene, Tmeff2 was overexpressed in TRAMP C1 murine prostate cancer cells and HEK293T cells, and the effects of overexpression on cellular growth and tumorigenicity were assessed. Tmeff2 overexpression in HEK293T cells almost completely abolished the ability of these cells to form colonies in soft agar and resulted in a 20-30% reduction in proliferation rates in these and TRAMP C1 cells, indicating that the gene may function as a tumor suppressor in prostate cancer cells. Moreover, although TMEFF2 overexpression alone did not induce apoptosis, it sensitized these cell lines to staurosporine or rapamycin-induced apoptosis, causing nearly a three-fold increase in the percentage of apoptotic cells. In order to assess the molecular mechanism(s) by which Tmeff2 may suppress cellular growth and tumorigenicity, we screened Tmeff2 affinity complexes by mass spectrometry to search for candidate functional partner(s) of Tmeff2. Our results showed an interaction with Sarcosine Dehydrogenase (SARDH) an enzyme involved in the metabolism of sarcosine. This interaction was further confirmed by co-immunoprecipitation analysis. Importantly, sarcosine has recently been described as a biomarker for prostate cancer as it was shown to be highly increased in prostate and metastatic prostate cancer. In addition, it may also play a role in the biology of the cancer since it promotes cell invasion when added to benign prostate epithelial cells. In summary, the results presented here suggest that Tmeff2 functions as a tumor suppressor for prostate cancer. Its interaction with SARDH may represent a mechanism by which Tmeff2 modulates tumorigenicity by altering the levels of sarcosine. Further analyses are necessary to determine the value of Tmeff2 as a prognostic marker. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3059.