Methylthioadenosine phosphorylase is required for prostate cancer growth in vitro and in vivo (766.2)

Abstract

Methylthioadenosine phosphorylase (MTAP) helps to sustain methionine metabolism, which, either directly or indirectly, plays a significant role in polyamine synthesis, DNA synthesis, and DNA methylation. MTAP is one of the most frequently deleted genes in human cancers, possibly contributing to genetic and epigenetic damage. Because prostate cells have an exceptionally high level of polyamine biosynthesis impinging on methionine metabolism, we investigated MTAP status in human prostate cancer (CaP). In contrast to many other types of cancer, MTAP was never deleted in CaP, as assessed in a sample of 13 cell lines by PCR and 75 CaP patients at different stages of the disease by tissue microarray analysis. In the context of folate deficiency, which stresses methionine metabolism, transcriptional up regulation of MTAP allowed CaP cells to adapt to the metabolic stress in order to provide sufficiency of key metabolites as assessed by HPLC analysis. We therefore hypothesized that MTAP may play an essential role in sustaining CaP growth. We treated a panel of CaP cell lines with a specific MTAP inhibitor. Consistent with MTAP’s importance in prostate cells’ metabolism, we found that the inhibitor was very effective in preventing CaP growth in vitro, with an IC50 between 0.7 and 1.4 µM. Finally, MTAP knock down in LNCaP cells prevented tumor establishment in nude mice. We conclude that MTAP plays a pivotal role in CaP growth and that, because of its importance specific to prostate cells, it could be a novel, ideal target for CaP therapy.Grant Funding Source: AICR American Institute for Cancer Research