Abstract B172: The metastasis suppressor NDRG1 up-regulates p21 in a p53-independent manner in cancer cells: A novel insight into its antitumor function

Abstract

Abstract A recently identified metastasis suppressor, N-myc downstream regulated gene-1 (NDRG1), has been shown to reduce the invasion and metastasis of numerous cancers including prostate (PC) and pancreatic (PaCa) (Maruyama Y et al. 2006 Cancer Res 66:6233–42) malignancies. Among its many functions, NDRG1 is involved in modulating differentiation, proliferation, and angiogenesis (Kovacevic Z & Richardson DR 2006 Carcinogenesis 27:2355–66). However, knowledge of the molecular function of NDRG1 is limited. We have recently discovered that NDRG1 is up-regulated in cancer cells by novel iron chelators being developed as anti-cancer agents in our lab (Richardson DR et al. Blood 2004 104:2967–75; Kovacevic Z et al. BBA 2008 1783:1981–92). These compounds were found to exhibit potent and selective anti-tumor activity in vivo (Richardson DR et al. PNAS USA 2006 103:14901–6). They also provide us with a unique opportunity to target this important metastasis suppressor in cancer tissues. The current study has focused on examining the molecular targets of NDRG1 in a number of different cancer cells to elucidate its anti-metastatic role. We further explored the efficacy of 2 novel iron chelators Bp4eT and Dp44mT, both of which up-regulate NDRG1, for the treatment of PaCa. We have identified for the first time that NDRG1 up-regulates protein levels of p21, a cyclin-dependant kinase inhibitor involved in controlling progression of the cell cycle. This effect was observed in three different cancer cell lines including PC3 and DU145 prostate cancer cells as well as H1299 lung cancer cells. This effect was transcriptional in PC3 and DU145 cells, with p21 mRNA levels increasing in response to NDRG1 expression in a p53-independent manner. The mechanisms involved in this effect may involve the p63 isoform Np63 and also a 60kDa MDM2 isoform, both of which are affected by NDRG1 in these cells and are able to modulate p21 expression. Further studies in PaCa have identified that NDRG1 is able to modulate the TGF-β pathway in this disease. Advanced PaCa is often associated with a deregulated TGF-β pathway leading to increased proliferation. We have found that the over-expression of NDRG1 in PaCa may restore normal TGF-β signaling, leading to reduced cell proliferation. In light of these results, our novel iron chelators Bp4eT and Dp44mT, both of which up-regulate NDRG1 in PaCa, were compared to gemcitabine, the current “gold standard” treatment for this disease. Our results show that both Bp4eT and Dp44mT were significantly more active against PaCa compared to gemcitabine in vitro, with >100,000-fold increase in activity in some cell lines. These data reveal for the first time the mechanisms behind the anti-tumor effects of NDRG1 in cancer cells. Furthermore, we have identified novel and potent anti-cancer agents which selectively target this important metastasis suppressor and have promising activity against PaCa. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B172.