The metastasis suppressor, Ndrg-1: a new ally in the fight against cancer.
Tumor metastasis is an important clinical problem, contributing to the majority of cancer-related deaths. The recent discovery of metastasis suppressor genes, such as N-myc downstream-regulated gene-1 (Ndrg-1), has introduced a novel approach to treating cancer and preventing metastasis. Ndrg-1 has been identified as a protein involved in the differentiation of epithelial cells. In addition, Ndrg-1 expression can be regulated by androgens and is involved in the pathology of the disease, Hereditary Motor and Sensory Neuropathy-Lom (HMSNL). However, one of the most well documented links between Ndrg-1 and pathophysiology is its association with inhibition of tumor metastasis. The expression of Ndrg-1 was found to be significantly downregulated in a variety of different neoplasms including breast, colon and prostate cancer. Furthermore, Ndrg-1 expression was shown to be negatively correlated with tumor metastasis. Studies in vitro and in vivo have demonstrated a significant reduction in the metastatic ability of cells overexpressing Ndrg-1. The ability of these cells to invade was also compromised. The Gleason grade of prostate and breast cancers was found to correlate with Ndrg-1 expression, with more advanced and poorly differentiated tumors having lower Ndrg-1 levels. Recently, Ndrg-1 expression was demonstrated to be regulated by cellular iron levels and induced by iron chelators. These latter compounds were recently identified as potential anticancer agents as they selectively prevent cancer cell proliferation and lead to apoptosis. The discovery that iron chelators also increase Ndrg-1 expression further augments their antitumor activity and provides a novel strategy for the treatment of cancer and its metastasis.
Kovacevic
Zaklina
Z
Iron Metabolism and Chelation Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia.
Richardson
Des R
DR
D001943:Breast Neoplasms / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007502:Iron Chelating Agents / Q000627:therapeutic use; D008297:Male; D009124:Muscle Proteins / Q000235:genetics; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009369:Neoplasms / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009419:Nerve Tissue Proteins / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics; D011506:Proteins / Q000235:genetics; D025521:Tumor Suppressor Proteins; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007502:Iron Chelating Agents; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D025521:Tumor Suppressor Proteins; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C466228:NDRG2 protein, human; C431706:NDRG3 protein, human; C431705:NDRG4 protein, human